Substituted 1,4,5,6-tetrahydro-2H-pyridazin-3-one and -3-thione compounds having lipoxygenase inhibitory activity

ABSTRACT

Pyridazinone, triazinone and oxapyridazinone compounds which are useful in inhibiting lipoxygenase enzymes, particularly 5-lipoxygenase.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of copending application Ser. No.210,806 filed June 28, 1988, now U.S. Pat. No. 4,970,210, issued Nov.13, 1990 which is a continuation-in-part of application Ser. No. 075,015filed July 17, 1987, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to compounds, compositions and methods forinhibiting lipoxygenase enzymes.

The lipoxygenases are a family of enzymes which catalyze the oxygenationof arachidonic acid. The enzyme 5-lipoxygenase converts arachidonic acidto 5-hydroperoxyeicosatetraenoic acid (5-HPETE). This is the first stepin the metabolic pathway yielding 5-hydroxyeicosatetraenoic acid(5-HETE) and the important class of potent biological mediators, theleukotrienes (LTs).

A variety of biological effects are believed to be associated with theseproducts from lipoxygenase metabolism of arachidonic acid, and they havebeen implicated as mediators in various disease states. For example, theLTs C₄ and D₄ are potent constrictors of human airways in vitro, andaerosol administration of these substances to non-asthmatic volunteersinduces broncho-constriction. LTB₄ and 5-HETE are potent chemotacticfactors for inflammatory cells such as polymorphonuclear leukocytes.They also have been found in the synovial fluid of rheumatoid arthriticpatients. Leukotrienes have also been implicated as important mediatorsin allergic rhinitis, psoriasis, adult respiratory distress syndrome,Crohn's disease, endotoxin shock, and ischemia induced myocardial injuryamong others. The biological activity of the LTs has been reviewed byLewis and Austen (J. Clinical Invest. 73,89, 1984 and by J. Sirois (Adv.Lipid Res. 21, 78, 1985).

Thus, lipoxygenase enzymes are believed to play an important role in thebiosynthesis of mediators of asthma, allergy arthritis, psoriasis, andinflammation. Blocking the activity of these enzymes will likelyinterrupt the pathological pathways believed to be involved in thesedisease states.

SUMMARY OF THE INVENTION

The present invention relates to compounds, compositions and a method ofinhibiting lipoxygenase enzymes, particularly 5-lipoxygenase, in amammal in need of such treatment by administering to such mammals acomposition that comprises a nontoxic pharmaceutically acceptablecarrier and a compound of Formula I, or its pharmaceutically acceptablesalt, in an amount effective to inhibit such activity. A compound of theinvention has a structure that corresponds to general Formula I below:##STR1## wherein A is selected from the group of C═O and C═S. B isselected from the group consisting of oxygen, NR₄ or CR₅ R₆. R₁ is anoptionally substituted aromatic carbocyclic or aromatic heterocyclicgroup having from one to three fused and non-fused ring systems, eachring having from five to seven atoms. The heteroatoms in theheterocyclic aromatics are selected from one or more of oxygen,nitrogen, and sulfur.

R₂ is a member selected independently at each occurrence from one ormore substituents of hydrogen, --NR₈ R₉, halogen, alkyl, --COOR₇,hydroxy, cyano, alkoxy, aryloxy, --NHCOR₁₀, alkenyl, aryl, arylalkyl,acyl, alkylthio, alkynyl, cycloalkyl, cycloalkenyl, deuterium, tritium,or an alkyl, cycloalkyl, alkenyl, cycloalkenyl or arylalkyl group whichis substituted with a group selected independently at each occurencefrom a group of the formula: halogen, --OR, --CN, --NRCONRR,--NR--CSNRR, --NRCOOR, alkythioalkoxy, --OCONRR, --OCOR,--(O(CHR)_(n))_(m) OR, --NRC(NR)NRR, --NRC(NCN)NRR, --C═NOR, --C═N--NRR,--COR, --CONRR, --CO₂ R, --CSNRR, --SOR, --R, SR, --SO₂ NRR, and --CF₃where R is independently selected at each occurence from: hydrogen,hydroxy, alkoxy, aryloxy, alkenyl, alkyl, arylalkyl, cycloalkyl, aryl oran optionally substituted aromatic carbocyclic or heterocyclic group asdefined above.

R₄ is a member selected from the group consisting of: hydrogen, alkyl,--COOR₇, hydroxy, alkoxy, aryloxy, arylalkyl, acyl, cycloalkyl,cycloalkenyl, deuterium, tritium, or an alkyl, cycloalkyl, alkenyl,cycloalkenyl or arylalkyl group which is substituted with a groupselected independently from the group consisting of halogen, --OR, --CN,--NRCONRR, --NR--CSNRR, --NRCOOR, alkylthioalkoxy, --OCONRR, --OCOR,--(O(CHR)_(n))_(m) OR, --NRC(NR)NRR, --NRC(NCN)NRR, --C═NOR, --C═N--NRR,--COR, --CONRR, --CO₂ R, --CSNRR, --SOR, --SO₂ R, SR, --SO₂ NRR, and--CF₃ where R is independently selected from the group consisting ofhydrogen, hydroxy, alkoxy, aryloxy, alkenyl, alkyl, arylalkyl,cycloalkyl, aryl or an optionally substituted aromatic carbocyclic orheterocyclic group as defined above;

m and n are numerals, each of which independently has a value of one to11.

Z is hydrogen, a pharmaceutically acceptable cation, or a metabolicallycleaveable group.

R₅ and R₆ are independently selected from the groups included in thedefinition for R₂ above.

R₇ is selected independently at each instance from alkyl,alkylaminoalkyl, alkylaryl, and aryl.

R₈ and R₉ are independently selected from hydrogen and alkyl.

R₁₀ is an alkyl group; with the proviso that when B=CH₂, A=CO, and R₂=Z=H, R₁ is other than phenyl.

Pharmaceutically acceptable salts of the above compounds are alsocontemplated.

A preferred embodiment of the present invention is where B=NR₄, and R₄=hydrogen, acyl and arylalkyl.

A more preferred group of the triazinone compounds are those of theformula: ##STR2## wherein Y═O or S. Z is hydrogen, a pharmaceuticallyacceptable salt or metabolically cleavable group.

R₁ is an unsubstituted or substituted phenyl having one or moresubstituents selected from the group consisting of alkyl, alkylthio,arylalkoxyoxy and halogen.

R₂ is selected from the group consisting of alkyl, alkanol,alkoxyalkoxyalkyl, and carboalkoxy.

R₄ is hydrogen, acyl, and arylalkyl.

The most preferred triazinone species are the following:

1-(3-chlorophenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-one

D,L-5-methyl-1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-one

D,L-5-methyl-1-(3-chlorophenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-one.

1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-one

1-(2-pyridyl)-2H,4H-tetrahydro-1,2,4-triazin-3-one

5-(2-methoxyethoxymethyl)-1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-one

1-(3-methylphenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-one

1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-thione

1-(3-chlorophenyl)-2H,4H-tetrahydro-1,2,4-triazine-3-thione

4-acetyl-1-phenyl-2H,4H-tetrahydro-1,2,4-triazine-3-one

The method of treatment for inhibiton of lipoxygenase enzymes, in amammal in need of such treatment, also contemplates the use of compoundsof Formula I wherein B=CH₂, A=CO , R₂ =Z=H and R₁ =phenyl.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates in one aspect to compounds and the processof making said compounds which are useful for inhibiting lipoxygenaseenzymes and as chemical intermediates for pharmaceuticals. Thisinvention particularly relates to compounds which inhibit5-lipoxygenase. Another aspect of the invention relates to compositionsand methods for inhibiting lipoxygenase enzymes in humans and animalhosts in need of such treatment.

A compound of the invention has a structure that corresponds to generalFormula I, below: ##STR3## wherein A is selected from C═O and C═S ; andB is a memeber selected from the group consisting of O, NR₄, and CR₅ R₆.

R1 is an aromatic carbocyclic or heterocyclic group having from one tothree fused or non-fused rings with each ring having from five to sevenatoms. The heteroatoms in the heterocyclic group are selected from oneor more of oxygen, nitrogen, and sulfur. Aromatic carbocycles areselected from such examples as, but not limited to: phenyl, naphthyl,biphenyl, anthracenyl, and biphenylene. Heterocyclic groups are selectedfrom such examples as, but not limited to; pyridyl, pyrimidyl,pyridazinyl, thienyl, furyl, imidazolyl, thiazolyl, indolyl, oxazole,trazole, tetrazole, quinolinyl, isoquinolinyl, benzimidazolyl,benzothiazolyl, benzthienyl, phenothiazinyl, benzoxazolyl andnaphthyridyl.

The aromatic carbocyclic or heterocyclic group can be unsubstituted orsubstituted with one or more substituents selected independently at eachoccurrence from the group consisting of hydrogen, deuterium, tritium,halogen, hydroxy, COOR₇, acyl, cyano, nitro, alkoxy, epoxy, aryl,aryloxy, arylalkoxy, alkyl, polyhaloalkyl, arylalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, alkylthio, alkylsulfonyl, arylthio,carboxaldehyde, heterocyclic group or an alkyl, cycloalkyl, alkenyl,cycloalkenyl or arylalkyl group which is substituted with a groupselected independently from the group consisting of --OR, --CN, halogen,--NRCONRR, --NRCSNRR, --NRCOOR, --OCONRR, --OCOR, --N(R)COR,--(O(CHR)_(n))_(m) OR, --NR--C(NR)NRR, --NRC(NCN)NRR, --C(R)═NOR, ═NOR,═N(R)NRR, --C(R)═N--NRR, --COR, --CONRR, --CO₂ R, --CSNRR, --SOR, --SO₂R, --SO₂ NRR, --CF₃ where R is independently selected from the groupconsisting of hydrogen, hydroxy, alkoxy, aryloxy, alkenyl, alkyl,cycloalkyl or an optionally substituted carbocyclic or heterocyclicgroup as defined above; m and n are numerals each of which independentlyhave values of 1-11.

R₂ is a member selected independently from the group consisting ofhydrogen, halogen, deuterium, hydroxy, tritium, cyano, --NR₈ R₉,NHCOR₁₀, COOR₇, --CONR₈ R₉, acyl, --C(R)═NOR, aryl, heterocyclic group,alkylthio, arylthio, arylalkyl, alkoxy, alkoxy(hydroxy)alkyl, aryloxy,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or an alkyl,cycloalkyl, alkenyl, cycloalkenyl or arylalkyl group which issubstituted with a group selected independently from the groupconsisting of halogen, --OR, --CN, --NR₈ R₉, --NRCONRR, --NRCSNRR,--NRCOOR, alkylthioalkoxy, --OCONRR, --OCOR, --(O(CHR)_(n))_(m) OR,--NRC(NR)NRR, --NRCOR, --NRC(NCN)NRR, --C(R)═NOR, --C(R)═N--NRR, --COR,--CONRR, --CO₂ R, CSNRR, --SOR, --SO₂ R, SR, --SO₂ NRR, --CF₃,--CH(NH₂)COOR, --O(CH ₂)_(n) COOR, --NH(CH₂)_(n) COOR, alkenyloxy,alkynyloxy, where R is independently selected from the group consistingof hydrogen, hydroxy, alkoxy, aryloxy, alkenyl, alkyl, arylalkyl,cycloalkyl, aryl or an optionally substituted aromatic carbocyclic orheterocyclic group as defined above, with the proviso that when B is Oor NR₄ then R₂ is not halogen, --NR₈ R₉, alkylthio, alkoxy, aryloxy orarylthio.

R₄ is a member selected from the group consisting of: hydrogen, alkyl,--COOR₇, hydroxy, alkoxy, aryloxy, arylalkyl, arylalkoxyalkyl, acyl,cycloalkyl, cycloalkenyl, deuterium, tritium, or an alkyl, cycloalkyl,alkenyl, cycloalkenyl or arylalkyl group which is substituted with agroup selected independently at each occurrence from the groupconsisting of halogen, --OR, --CN, --NRCONRR, --NRCCSNRR, --NRCOOR,alkylthioalkoxy, --OCONRR, --OCOR, --N(R)COR, --(O(CHR)_(n))_(m) OR,--NRC(NR)NRR, --NRC(NCN)NRR, --C(R)═NOR, --C(R)═N--NRR, --COR, --CONRR,--CO₂ R, --CSNRR, --SOR, --SO₂ R, SR, --SO₂ NRR, and --CF₃ where R isindependently selected from the group consisting of hydrogen, hydroxy,alkoxy, aryloxy, alkenyl, alkyl, arylalkyl, cycloalkyl, aryl or anoptionally substituted aromatic carbocyclic or heterocyclic group asdefined above; m and n are as defined above.

R₇ is selected independently from the group consisting of alkyl,alkylaminoalkyl, alkylaryl, and aryl.

R₈ and R₉ are independently selected from hydrogen and alkyl.

Z is hydrogen, a pharmaceutically acceptable cation, or is metabolicallycleaved to provide the corresponding hydrogen or salt compound.

R₁₀ is an alkyl group; and the pharmaceutically acceptable saltsthereof; with the proviso that when B=CH₂, A=CO, and R₂ =Z=H, R₁ isother than phenyl.

The term "metabolically cleaveable group" refers to groups which can becleaved from the molecule by metabolic processes and be substituted witha hydrogen, a salt or form a group which yields an active enzymeinhibitor when the cleaveable group is removed from the molecule.Examples of metabolically cleaveable groups include acetyl,methoxycarbonyl, benzyl, benzoyl, COR, COOR, --CH₂ COOR, CONRR, --CH₂CONRR, --CH₂ OR, and --CH₂ SR where R is selected independently at eachoccurrence from alkyl, aryl, arylalkyl or an aryl substituted with oneor more of alkyl, halogen, hydroxy or alkoxy.

A preferred embodiment of the present invention is the triazinone groupof compounds, in which B=NR₄, and R₄ =hydrogen, acyl and arylalkyl.

A more preferred group of the triazinone compounds are those of theformula: ##STR4## wherein Y═O or S. Z is hydrogen, a pharmaceuticallyacceptable salt or metabolically cleavable group.

R₁ is an unsubstituted or substituted phenyl having one or moresubstitutents selected from the group consisting of alkyl, alkylthio,arylalkyloxy and halogen.

R₂ is selected from the group consisting of alkyl, alkanol,alkoxyalkoxyalkyl, and carboalkoxy.

R₄ is hydrogen and acyl.

The most preferred group of triazinone compounds are the followingspecies:

1-(3-chlorophenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-one.

D,L-5-methyl-1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-one.

D,L-5-methyl-1-(3-chlorophenyl)2H,4H-tetrahydro-1,2,4-triazin-3-one.

1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-one.

1-(2-pyridyl)-2H,4H-tetrahydro-1,2,4-triazin-3-one.

5-(2-methoxyethoxymethyl)-1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-one

1-(3-methylphenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-one.

1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-thione.

1-(3-chlorophenyl)-2H,4H-tetrahydro-1,2,4-triazine-3-thione.

4-acetyl-1phenyl-2H,4H-tetrahydro-1,2,4-triazine-3-one

The replacement of any carbon atom with carbon isotopes C13 or C14 aswell as the replacement of any hydrogen by either deuterium or tritium,on the aromatic carbocylic or heterocyclic rings or the R₂ group, isalso contemplated. Also within the scope of this invention are theoptical isomers, enatiomers and racemic mixtures of the disclosedcompounds herein, for use as lipoxygenase inhibitors.

Another aspect of this invention is a composition containing aneffective amount of a compound of Formula I in combination with apharmaceutically acceptable carrier, adjuvant or diluent. The presentinvention further contemplates a method of treatment. Here, an effectiveamount of an above-noted composition is administered to an animal orhuman host.

Examples of compounds which can be administered according to the methodof this invention and/or are novel compounds of this invention includethe following:

1-(3'-cyanophenyl)-2H-tetrahydropyridazin-3-one

1-(4'-cyanophenyl)-2H-tetrahydropyridazin-3-one

1-(3'-methoxyphenyl)-2H-tetrahydropyridazin-3-one

1-(4'-methoxyphenyl)-2H-tetrahydropyridazin-3-one

1-(4'-butoxyphenyl)-2H-tetrahydropyridazin-3-one

1-(4'-phenoxyphenyl)-2H-tetrahydropyridazin-3-one

1-(4'-trifluoromethylphenyl)-2H-tetrahydropyridazin-3-one

1-(3'-trifluoromethylphenyl)-2H-tetrahydropyridazin-3-one

1-(2'-ethylphenyl)-2H-tetrahydropyridazin-3-one

1-(3'-ethylphenyl)-2H-tetrahydropyridazin-3-one

1-(4'-ethylphenyl)-2H-tetrahydropyridazin-3-one

1-(4'-butylphenyl)-2H-tetrahydropyridazin-3-one

1-(4'-tert-butylphenyl)-2H-tetrahydropyridazin-3-one

1-(3'-pentylphenyl)-2H-tetrahydropyridazin-3-one

1-(4'-octylphenyl)-2H-tetrahydropyridazin-3-one

1-(3'-ethoxycarbonylphenyl)-2H-tetrahydropyridazin-3-one

1-(4'-ethoxycarbonylphenyl)-2H-tetrahydropyridazin-3-one

1-(3'-hydroxymethylphenyl)-2H-tetrahydropyridazin-3-one

1-(4'-methylsulfonylphenyl)-2H-tetrahydropyridazin-3-one

1-(3'-methanalphenyl)-2H-tetrahydropyridazin-3-one

1-(5'-indanyl)-2H-tetrahydropyridazin-3-one

1-(5'-tetrahydronaphthyl)-2H-tetrahydropyridazin-3-one

1-(3-dibenzofuranyl)-2H-tetrahydropyridazin-3-one

1-(3',5'-dimethylphenyl)-2H-tetrahydropyridazin-3-one

1-(2',6'-dimethylphenyl)-2H-tetrahydropyridazin-3-one

1-(3',5'-dichlorophenyl)-2H-tetrahydropyridazin-3-one

1-(2',3'-difluorophenyl)-2H-tetrahydropyridazin-3-one

1-(2',6'-difluorophenyl)-2H-tetrahydropyridazin-3-one

1-(2',5'-difluorophenyl)-2H-tetrahydropyridazin-3-one

1-(3',5'-difluorophenyl)-2H-tetrahydropyridazin-3-one

1-(4'-fluoro-3'-trifluoromethylphenyl)-2H-tetrahydropyridazin-3-one

1-(3'5'-bistrifluoromethylphenyl)-2H-tetrahydropyridazin-3-one

1-(4'-bromo-3'-methylphenyl)-2H-tetrahydropyridazin-3-one

1-(4'-(2-diethylaminoethyl)carboxyl)-2H-tetrahydropyridazin-3-one

1-(3,4,5-trichlorophenyl)-2H-tetrahydropyridazin-3-one

1-(N-ethyl-3-dibenzopyrolyl)-2H-tetrahydropyridazin-3-one

1-(3'-cyanophenyl)-4-methyl-2H-tetrahydropyridazin-3-one

1-phenyl-4-butyl-2H-tetrahydropyridazin-3-one

1-phenyl-4-benzyl-2H-tetrahydropyridazin-3-one

1-phenyl-5-butyl-2H-tetrahydropyridazin-3-one

1-(4'-phenoxyphenyl)-4-methyl-2H-tetrahydropyridazin-3-one

1-(3-methylphenyl-2H-tetrahydropyridazin-3-one

1-(2'-methylphenyl)-2H-tetrahydropyridazin-3-one

1-(4'-methylphenyl)-2H-tetrahydropyridazin-3-one

1-(2'-chlorophenyl)-2H-tetrahydropyridazin-3-one

1-(3'-chlorophenyl)-2H-tetrahydropyridazin-3-one

1-(4'-chlorophenyl)-2H-tetrahydropyridazin-3-one

1-(3'-bromophenyl)-2H-tetrahydropyridazin-3-one

1-(2'-fluorophenyl)-2H-tetrahydropyridazin-3-one

1-(3'-fluorophenyl)-2H-tetrahydropyridazin-3-one

1-(4'-fluorophenyl)-2H-tetrahydropyridazin-3-one

1-(2-benzoxazole)-2H-tetrahydropyridazin-3-one

1-(2-pyrimidyl)-2H-tetrahydropyridazin-3-one

1-(2-pyridyl)-2H-tetrahydropyridazin-3-one

1-(2,4-dinitrophenyl)-2H-tetrahydropyridazin-3-one

1-phenyl-4-(2-propenyl)-2H-tetrahydropyridazin-3-one

1-phenyl-4-(2-methyl-2-propenyl)-2H-tetrahydropyridazone

1-phenyl-4-ethyloxymethyl-2H-tetrahydropyridazone

1-phenyl-4-benzyloxymethyl-2H-tetrahydropyridazone

1-phenyl-4-methylthiomethyl-2H-tetrahydropyridazone

1-phenyl-4-phenylthiomethyl-2H-tetrahydropyridazone

1-phenyl-4-(3-methyl-1-oxo-but-2-enyl)-2H-tetrahydropyridazin-3-one

1-phenyl-4-(hydroxymethylphenyl)-2H-tetrahydropyridazin-3-one

1-(3-chlorophenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-one

D,L-5-methyl-1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-one

D,L-5-methyl-1-(3-chlorophenyl)2H,4H-tetrahydro-1,2,4-triazin-3-one

1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-one

5-(2-methoxyethoxymethyl)-1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-one

1-(2-pyridyl)-2H,4H,tetrahydro-1,2,4-triazine-3-one

1-(4-methylphenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-one

1-(2-methylphenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-one

1-(3-methylphenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-one

4-phenyl-3H-trihydro-1,3,4-oxadiazin-2-one

1-phenyl-2-benzyloxymethyl-2H-tetrahydropyridazin-3-one

1-phenyl-2-benzyl-2H-tetrahydropyridazin-3-one

1-phenyl-2-carbomethoxy-2H-tetrahydropyridazin-3-one

1-phenyl-2-propionyl-2H-tetrahydropyridazin-3-one

1-phenyl-2-benzoyl-2H-tetrahydropyridazin-3-one

1-phenyl-2-methoxycarbonylmethyl-2H-tetrahydropyridazin-3-one

1-(3'-benzyloxymethylphenyl)-2-benzyl-2H-tetrahydropyridazin-3-one

1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-thione

1-(3-chlorophenyl)-2H,4H-tetrahydro-1,2,4-triazine-3thione

1-phenyl-2H-tetrahydropyridazin-3-thione

1-(3'-fluorophenyl)-2H-tetrahydropyridazin-3-thione

1-(3'-methylphenyl)-2H-tetrahydropyridazin-3-thione.

The term "alkyl" is used herein to mean straight and branched chainradicals of 1-12 carbon atoms, including but not limited to, methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,and the like.

The term "alkenyl" is used herein to mean straight and branched chainunsaturated radicals of 1-12 carbon atoms, including, but not limited toethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, and the like.

The term "alkoxy" is used herein to mean straight and branched chainedoxygen ether radicals of 1-12 carbon atoms, including, but not limitedto methoxy, ethoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy,tert-butoxy, and the like.

The term "carbonyl" or "alkoyl" or "acyl" is used herein to mean COMwherein M is a straight or branched radical, phenyl or benzyl including,but not limited to, formyl, acetyl, propionyl, butyryl, isobutyryl,pivaloyl, benzoyl, phenyalacetyl, and the like.

The term "aryl" is used herein to mean substituted and unsubstitutedaromatic radicals, including, but not limited to phenyl, 1-naphthyl,2-naphthyl, and the like.

The terms "halo" and "halogen" as used herein refer to radicals derivedfrom the elements fluorine, chlorine, bromine, and iodine.

The term "aryloxy" as used herein refers to substituted or unsubstitutedaryl ethers including, but not limited to phenoxy, 1-naphthoxy,2-naphthoxy, and the like.

The term "arylalkoxy" as used herein refers to an alkoxy radicalsubstituted with an aryl group, including, but not limited to benzyloxyand the like.

The term "arylalkoxyalkyl" as used herein refers to an alkyl radicalsubstituted by an arylalkoxy group.

The term "alkoxy(hydroxy)alkyl" as used herein refers to an alkylradical substituted by an alkoxy group and a hydroxy group including,but not limited to 1-hydroxy-2-methoxy-ethyl and the like.

The term "arylalkyl" as used herein refers to substituted orunsubstituted aryl alkyl radicals including but not limited tophenylmethyl (benzyl), 1-phenylethyl, 2-phenylethyl, 1-naphthylethyl.

The term "pharmaceutically acceptable cation" or "salt" is used hereinto mean the non-toxic cations based on the alkali and alkaline earthmetals, such as sodium, lithium, potassium, magnesium, and the like, aswell as those based on non-toxic ammonium, quaternary ammonium, andamine cations, including, but not limited to, ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, ethylamine and the like.

The term "alkylthioalkoxy" as used herein refers to --(CH₂)_(s)D(CH₂)_(n) G(CH₂)_(p) CH₃ wherein D is O or S and G is S when D is O orG is O when D is S, and s and n are numerals independently having avalue from 1 to about 11 and p is a numeral having a value from 0 toabout 11.

The term "alkoxyalkoxyalkyl" as used herein refers to --CH₂(O(CHR)_(n))_(m) OR wherein R is as defined above and n and m arenumerals independently having a value form 1 to about 11, including, butnot limited to, methoxymethoxy and methoxyethoxyethoxy.

The term "alkylthioalkyl" as used herein refers to a sulfur ether,including groups of the formula --S(CH₂)_(n) CH₃ where n is as definedabove.

The term "arylthio" as used herein refers to groups of the formula--S(Ar) where Ar is an aryl group.

The term "arylsulfoxide" as used herein refers to a group of the formula--SO(Ar) where Ar is an aryl group.

The term "polyhaloalkyl" as used herein refers to an alkyl radical inwhich two or more hydrogens are replaced by halogen, including but notlimited to, trifluoromethyl, dichloroethyl and the like.

The terms "arylsulfonyl" and "alkylsulfonyl" as used herein refer to--SO₂ Q where Q is an aryl group or an alkyl group, respectively.

The term "alkylaminoalkyl" as used herein refers to an alkyl groupsubstituted with an amino group mono-or disubstituted with an alkylgroup. Alkylamino-alkyl groups include methylaminomethyl and the like.

The terms "alkenyloxy" and "alkynyloxy" as used herein refer to alkoxyradicals in which the chain of carbon atoms contains one or more doubleor triple bonds, respectively.

Formulation of the Pharmaceutical Composition

This invention also provides for compositions in unit dosage form forthe inhibition of lipoxygenase activity in a human or lower animal hostin need of such treatment, comprising a compound of this invention andone or more non-toxic pharmaceutically acceptable carriers, adjuvants orvehicles which are collectively referred to herein as carriers. Theamount of active ingredient that may be combined with such materials toproduce a single dosage form will vary depending upon various factors,as indicated above.

A variety of materials can be used as carriers in a composition of thisinvention, are available i the pharmaceutical arts. Injectablepreparations, such as oleaginous solutions, suspensions or emulsions,may be formulated according to know art, using suitable dispersing orwetting agents and suspending agents, as needed. The sterile injectablepreparation may employ a non-toxic parenterally acceptable diluent orsolvent as, for example, sterile nonpyrogenic water or 1,3-butanediol.Among the other acceptable vehicles and solvents that may be employedare 5% dextrose injection, Ringer's injection and isotonic sodiumchloride injection (as described in the USP/NF). In addition, sterile,fixed oils are conventionally employed as solvents or suspending media.For this purpose, any bland fixed oil may be used, including syntheticmono-, di- or triglycerides. Fatty acids such as oleic acid can also beused in the preparation of injectable compositions.

Suppositories for rectal administration of the compound of thisinvention can be prepared by mixing the drug with suitablenon-irritating excipient such as cocoa butter and polyethylene glycols,which are solid at ordinary temperatures but liquid at body temperatureand which, therefore, melt in the rectum and release the drug.

Solid dosage forms for oral administration include capsules, tablets,pills, troches, lozenges, powders and granules. In such solid dosageforms, the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, pharmaceutical adjuvant substances,e.g., stearate lubricating agents. In the case of capsule, tablets andpills, the dosage forms may also comprise buffering agents. Solid oralpreparations can also be prepared with enteric or other coatings whichmodulate release of the active ingredients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirscontaining inert nontoxic diluents commonly used in the art, such aswater and alcohol. Such compositions may also comprise adjuvants, suchas wetting agents, emulsifying, suspending, sweetening, flavoring andperfuming agents.

Method of Treatment

This invention provides a method of treatment of inhibitinglipoxygenase, in particular 5-lipoxygenase activity, in a human or loweranimal host in need of such treatment which method comprisesadministration to the human or lower animal host of a previouslydescribed composition that contains a compound of Formula I and also thecompounds wherein B=CH₂, A=CO , and R₂ =Z=H and R₁ =phenyl, in an amounteffective to inhibit lipoxygenase activity in the host. The compounds ofthe present invention may be administered orally, parenterally ortopically in dosage unit formulations containing conventional nontoxicpharmaceutically acceptable carriers, adjuvants and vehicles as desired.

The term parenteral as used herein includes subcutaneous, intravenous,intraarterial injection or infusion techniques, without limitation. Theterm "topically" encompasses administration rectally and by inhalationspray, as well as by the more common routes of the skin and mucousmembranes of the mouth and nose.

Total daily dose of the compounds of this invention administered to ahost in single or divided doses maybe in amounts, for example, of fromabout 0.001 to about 100 mg/kg body weight daily and more usually 0.01to 10 mg/kg/day. Dosage unit compositions may contain such amounts ofsuch submultiples thereof as may be used to make up the daily dose. Itwill be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors, including thebody weight, general health, sex, diet, time and route ofadministration, rates of absorption and excretion, combination withother drugs and the severity of the particular disease being treated.

Synthesis of the Compounds I) Pyridazinone Synthesis

Pyridazinone compounds of this invention can be prepared by reactionSchemes I-III below. In most cases, any one of the three schemes can beused to make any of the exemplary pyridazinone compounds below. However,for some compounds, either only one of the specific Schemes I-III can beused, or one of the specific Schemes I-III produces the compound in apurer form or in a higher yield than the other Schemes. Thus, theExamples are grouped according to preferred synthetic scheme. Thecompounds of Examples following Scheme I are preferably made accordingto Scheme I, and so on. When not specified all temperature ranges are indegress centigrade.

a) Scheme I

Pyridazinones of the general Formula II are prepared by the sequence ofreactions outlined in Scheme I. The meanings of R₁, R₂ and the likecorrespond to the definitions provided above. A primary amine (1) iscondensed with a substituted ethyl bromobutyrate (2) usingdiisopropylethylamine (for example, EtN(iPr)₂) as a base to yield thesecondary amine (3). N-Nitrosation yields the intermediate N-nitrosocompound (4). Reduction of (4) with zinc powder produces theintermediate hydrazine (5) which is intramolecularly cyclized bytreatment with an appropriate base (such as sodium methoxide, magnesiumethoxide, or potassium tert-butoxide) to produce the pyridazinonestructure II. The application of substituted ethylbromobutyrates (2) isdescribed in several of the specific examples which follow. ##STR5##

EXAMPLE 1 1-(3'-cyanophenyl)-2H-tetrahydropyridazin-3-one Formula II, R₁=3-cyanophenyl; R₂ =H

a) Ethyl 4-(3'-aminobenzonitrile) butyrate

3-Aminobenzonitrile (24.7 g, 0.21 mole), diisopropylethylamine (27.0 g,0.21 mole) and ethyl 4-bromobutyrate (40.8 g, 0.21 mole) were dissolvedin benzene (150 mL), and the mixture was refluxed with stirring under anitrogen atmosphere for five days. The mixture was allowed to cool toroom temperature and water (100 mL) was added. The organic layer wasseparated, dried over MgSO₄, filtered and evaporated to give a residue(50.7 g). A sample was crystallized from hexane to give colorlesscrystals, mp 62°-63° C.

Mass spectrum M+=232.

b) Ethyl 4-(3'-cyano-N-nitosoaniline) butyrate.

The residue from part a (46 g) was suspended in a solution of water (200mL) containing concentrated HCl (30 mL), and was cooled to 5° C. Withefficient mechanical stirring, a solution of NaNO₂ (14.0 g) in water (50mL) was added. The mixture was stirred for an additional one hour at 5°C. and then extracted with benzene (3×100 mL). The combined organicextract was evaporated to give an oily residue (47.5 g).

c) Ethyl 4-(3'-cyano-N-aminoaniline) butyrate.

The residue from part b (47 g) was dissolved in acetic acid (60 mL) andadded dropwise to a mechanically stirred suspension of zinc dust (56.0g) in water (90 mL). The temperature of the mixture was controlled notto exceed 22° C. by external cooling with an ice bath. After theaddition was complete the mixture was warmed to 80° C. for 20 min. andthen allowed to cool to room temperature. Water (200 mL) anddichloromethane (200 mL) was added and with stirring the pH of themixture was adjusted to 6-7 with 6N NaOH. The solution was filtered (toremove excess zinc) and the solids were washed with dichloromethane (50mL). The combined filtrate was transferred to a separatory funnel andthe layers were separated. The aqueous layer was extracted withdichloromethane (2×50 mL). The combined organic extract was dried overMgSO₄, filtered and evaporated to provide a residue (41.6 g).

d) 1(3'-cyanopnenyl)-2H-tetrahydropyridazin-3-one

The residue from part c (41 g) was dissolved in tetrahydrofuran (90 mL)and with stirring under nitrogen potassium tert-butoxide (3.0 g) wasadded. The mixture was refluxed for two hours, allowed to cool, andwater (100 mL) was added. The pH of the solution was adjusted to 6 with3N HCl, and the mixture was extracted with dichloromethane (2×100 mL).The combined organic extract was dried over MgSO₄, filtered andevaporated to give a solid product (9.7 g), mp 148°-149° C.

¹ H NMR (300 MHz, CDCl₃) 1.97-2.08 (2 H, m), 2.43 (2 H, t), 3.77 (2 H,t), 7.20-7.28 (3 H, m), 7.37-7.43 (1 H, m), 8.37 (1 H, br s).

Mass spectrum: M+=201

Anal.Calc'd. for C11H11N30 : C, 65.66; H, 5.51; N, 20.88.

Anal. Found : C, 65.30; H,5.57; N, 20.54.

EXAMPLE 2 1- (4'-cyanophenyl)-2H-tetrahydropyridazin-3-one (Formula II,R₁ =4-cyanophenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 4-aminobenzonitrile instead of3-aminobenzonitrile as R₁ -NH₂.

mp 149°-154° C.

¹ H NMR(300 MHz,CDCl₃)2.02-2.14 (2 H, m), 2.41 (2H, t), 3.80 (2H, t),6.99-7.06 (2H, m), 7.54-7.61 (2H, m), 8.22 (1H, br s).

Mass spectrum: M+=201

Anal.Calc'd. for C₁₁ H₁₁ N₃ O : C, 65.66; H, 5.51; N, 20.88.

Anal. Found : C, 65.84; H,5.56; N, 20.62.

EXAMPLE 3 1- (3'-methoxyphenyl)-2H-tetrahydropyridazin-3-one (FormulaII, R₁ =3-methoxyphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 3-methoxyaniline instead of3-aminobenzonitrile as R₁ -NH₂.

mp 95.5° C.

¹ H NMR(300 MHz,CDCl₃) 1.97 (2H, m), 2.42 (2H, t, J=7.5 Hz), 3.69 (2H, tJ=6.5 Hz), 3.79 (3H, s), 6.57 (3H, m), 7.22 (1H, t, J=8 Hz), 7.47 (1H,br s).

Mass spectrum: M+=206

EXAMPLE 4 1-(4'-methoxyphenyl)-2H-tetrahydropyridazin-3-one (Formula II,R₁ =4-methoxyphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 4-methoxyaniline instead of3-aminobenzonitrile as R₁ -NH₂.

mp 78° C.

¹ H NMR (300 MHz,CDCl₃) 1.90 (2H, m), 2.46 (2H, t, J=7.5 Hz), 3.62 (2H,t, J=6.3 Hz), 3.78 (3H, s), 6.90 (4H, m), 7.62 (1H, br s).

Mass spectrum: M+=206

Anal.Calc'd. for C₁₁ H₁₄ N₂ O₂ : C, 64.06; H, 6.84; N, 13.58.

Found : C, 64.05; H,6.92; N, 13.60.

EXAMPLE 5 1-(4'-butoxyphenyl)-2H-tetrahydropyridazin-3-one (Formula II,R₁ =4-butoxyphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 4-butoxyaniline instead of3-aminobenzonitrile as R₁ -NH₂.

mp 68°-69° C.

¹ H NMR(300 MHz,CDCl₃) 0.97 (3H, t), 1.42-1.56 (2H, m), 1.70-1.80 (2H,m), 1.84-1.94 (2H, m), 2.46 (2H, t,), 3.61 (2H, t), 3.92 (2H, t),6.81-6.88 (2H, m), 6.90-6.95 (2H,m), 7.43 (1H, s).

Mass spectrum: M+=248

Anal.Calc'd. for C₁₄ H₂₀ N₂ O₂ : C, 67.71; H, 8.12; N, 11.28.

Found : C, 67.51; H, 8.12; N, 11.16.

EXAMPLE 6 1-(4'-phenoxyphenyl)-2H-tetrahydropyridazin-3-one (Formula II,R₁ =4-phenoxyphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 4-phenoxyaniline instead of3-aminobenzonitrile as R₁ -NH₂.

mp 160° C.

¹ H NMR(300 MHz,CDCl₃) 1.96 (2H, m), 2.47 (2H, t), 3.67 (2H, t),6.90-7.11 (7H, m), 7.27-7.37 (2H,m), 7.61 (1H,s).

Mass spectrum: M+=268

Anal.Calc'd for C₁₆ H₁₆ N₂ O₂ : C, 71.62; H, 6.01; N, 10.44.

Found : C, 71.49; H, 5.95; N, 10.16.

EXAMPLE 7 1-(4'-trifluoromethylphenyl)-2H-tetrahydropyridazin-3-one(Formula II, R₁ =4-trifluoromethylphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 4-trifluoromethylaniline insteadof 3-aminobenzonitrile as R₁ -NH₂.

mp 89° C.

¹ H NMR(300 MHz,CDCl₃) 1.98-2.11 (2H, m), 2.41 (2H, t), 3.78 (2H, t),7.06 (2H, d), 7.55 (2H, d), 7.89 (1H, brs).

Mass spectrum: M+=244

Anal.Calc'd. for C₁₁ H₁₁ F₃ N₂ O : C, 54.10; H, 4.54; N, 11.47.

Found : C, 54.20; H, 4.57; N, 11.33.

EXAMPLE 8 1-(3'-trifluoromethylphenyl)-2H-tetrahydropyridazin-3-one(Formula II, R₁ =3-trifluoromethylphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 3-trifluoromethylaniline insteadof 3-aminobenzonitrile as R₁ -NH₂.

mp 130° C.

¹ H NMR(300 MH_(z),CDCl₃) 2.0 (2H, m), 2.43 (2H, t, J=7.5 Hz), 3.76 (2H,t, J=6 Hz), 7.2 (3H, m), 7.4 (1H, m), 8.07 (1H, b rs).

Mass spectrum: M+=244

EXAMPLE 9 1-(2'-ethylphenyl)-2H-tetrahydropyridazin-3-one (Formula II,R₁ =2-ethylphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 2-ethylaniline instead of3-aminobenzonitrile as R₁ -NH₂.

mp 135° C.

¹ H NMR(300 MHz,CDCl₃) 1.27 (3H, t), 1.78-1.87 (2H, 2), 2.60 (2H, t),2.70 (2H, q), 3.33-3.40 (2H, m), 7.08-7.26 (4H, m), 7.32 (1H, s).

Mass spectrum: M+=204

Anal.Calc'd for C₁₂ H₁₆ N₂ O : C, 70.56; H, 7.89; N, 13.71.

Found : C, 71.02; H, 7.95; N, 13.74.

EXAMPLE 10 1-(3'-ethylphenyl)-2H-tetrahydropyridazin-3-one (Formula II,R₁ =3-ethylphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 3-ethylaniline instead of3-aminobenzonitrile as R₁ -NH₂.

mp 90° C.

¹ H NMR(300 MHz,CDCl₃) 1.22 (3H, t), 1.90-2.00 (2H, m), 2.43 (2H, t),2.58-2.66 (2H, m), 6.78-6.85 (3H, m), 7.17-7.25 (1H, m), 7.57 (1H, brs).

Mass spectrum: M+=204

Anal.Calc'd. for C₁₂ H₁₆ N₂ O : C, 70.56; H, 7.89; N, 13.71.

Found : C, 70.38; H, 7.87; N, 13.33.

EXAMPLE 11 1-(4'-ethylphenyl)-2H-tetrahydropyridazin-3-one (Formula II,R₁ =4-ethylphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 4-ethylaniline instead of3-aminobenzonitrile as R₁ -NH₂.

mp 76° C.

¹ H NMR(300 MHz,CDCl₃) 1.22 (3H, t), 1.85-1.98 (2H, m), 2.43 (2H, t),2.60 (2H, q), 3.67 (2H, t), 6.89-6.96 (2H, m), 7.09-7.16 (2H, m), 7.61(1H, s).

Mass spectrum: M+=204

Anal Calc'd. for C₁₂ H₁₆ N₂ O : C, 70.56; H 7.89; N, 13.71.

Found : C, 70.39; H, 8.06; N, 13.65

EXAMPLE 12 1-(4'-butylphenyl)-2H-tetrahydropyridazin-3-one (Formula II,R₁ =4-butylphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 4-butylaniline instead of3-aminobenzonitrile as R₁ -NH₂.

mp 84° C.

¹ H NMR(300 MHz,CDCl₃) 0.93 (3H, t, J=7 Hz), 1.35 (2H, m), 1.58 (2H, m),1.93 (2H, m), 2.45 (2H, t, J=7 Hz), 2.57 (2H, t, J=8 Hz), 3.68 (2H, t,J=6 Hz), 6.92 (2H, d, J=8 Hz), 7.12 (2H, d, J=8 Hz), 7.48 (1H, br s).

Mass spectrum: M+=232

EXAMPLE 13 1-(4'-tert-butylphenyl)-2H-tetrahydropyridazin-3-one (FormulaII, R₁ =4-tert-butylphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 4-tert-butylaniline instead of3-aminobenzonitrile as R₁ -NH₂.

mp 162° C.

¹ H NMR(300 MHz,CDCl₃) 1.3 (9H, s), 1.87-1.97 (2H, m), 2.43 (2H, t,J=7.5 Hz), 3.67 (2H, t, J=6.5 Hz), 6.93 (2H, m), 7.28 (2H, m), 7.60 (1H,br s).

Mass spectrum: M+=232

EXAMPLE 14 1-(3'-pentylphenyl)-2H-tetrahydropyridazin-3-one (Formula II,R₁ =3-pentylphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 3-pentylaniline instead of3-aminobenzonitrile as R₁ -NH₂.

¹ H NMR(300 MHz,CDCl₃) 0.85 (3H, t, J=7 Hz), 1.25 (6H, m), 1.65 (3H, m),1.90 (1H, m), 2.18 (1H, m), 2.38 (1H, m), 3.75 (2H, m), 6.95 (2H, m),7.15 (1H, br s), 7.25 (2H, m).

Mass spectrum: M+=246

EXAMPLE 15 1-(4'-octylphenyl)-2H-tetrahydropyridazin-3-one (Formula II,R₁ =4-octylphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 4-octylaniline instead of3-aminobenzonitrile as R₁ -NH₂.

mp 68° C.

¹ H NMR(300 MHz,CDCl₃) 0.88 (3H, t, J=7 Hz), 1.28 (10H, m), 1.58 (2H,m), 1.94 (2H, m), 2.44 (2H, t, J=7.5 Hz), 2.54 (2H, t, J=7.5 Hz), 3.67(2H, t, J=6 Hz), 6.92 (2H, m), 7.11 (2H, m), 7.32 (1H, br s).

Mass spectrum: M+=288

EXAMPLE 16 1-(3'-ethoxycarbonylphenyl)-2H-tetrahydropyridazin-3-one(Formula II, R₁ =3-ethoxycarbonylphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 3-ethoxycarbonylaniline instead of3-aminobenzonitrile as R₁ -NH₂.

mp 90° C.

¹ H NMR(300 MHz,CDCl₃) 1.40 (2H, t, J=7.5 H_(z)), 1.95-2.05 (2H, m),2.43 (2H, t, J=7.5 Hz), 3.78 (2H, t, J=6.5 Hz), 4.38 (2H, q, J=7.5 Hz),7.22 (1H, m), 7.47 (1H, m), 7.54 (1H, br), 7.64 (1H, m).

Mass spectrum: M+=248

EXAMPLE 17 1-(4'-ethoxycarbonylphenyl)-2H-tetrahydropyridazin-3-one(Formula II, R₁ =4-ethoxycarbonylphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 4-ethoxycarbonylaniline instead of3-aminobenzonitrile as R₁ -NH₂.

mp 74° C.

¹ H NMR(300 MHz,CDCl₃) 1.38 (3H, t), 1.98-2.10 (2H, m), 2.49 (2H, t),3.79 (2H, t), 4.30-4.42 (2H, q), 6.97-7.04 (2H, m), 7.90-8.10 (3H, m).

Mass spectrum: M+=248

Anal.Calc'd. for C₁₃ H₁₆ N₂ O₃ : C, 62.89; H, 6.50; N, 11.28.

Found : C, 60.81; H, 6.39; N, 11.21

EXAMPLE 18 1-(3'-hydroxymethylphenyl)-2H-tetrahydropyridazin-3-one(Formula II, R₁ =3-hydroxymethylphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 3-hydroxymethylaniline instead of3-aminobenzonitrile as R₁ -NH₂.

mp 128° C.

¹ H NMR(300 MHz, DMSO-d₆) 1.81 (2H, m), 2.16 (2H, t, J=7.5 Hz), 3.65(2H, t, J=6 Hz), 4.45 (2H, d, J=6 Hz), 5.17 (1H, t, J=6 Hz), 6.80-6.85(2H, m), 6.95 (1H, s), 7.21 (1H, t, J=8 Hz), 9.73 (1H, s).

Mass spectrum: M+=206

EXAMPLE 19 1-(4'-methylsulfonylphenyl)-2H-tetrahydropyridazin-3-one(Formula II, R₁ =4-methylsulfonylphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 4-methylsulfonylaniline instead of3-aminobenzonitrile as R₁ -NH₂.

mp 147° C.

¹ H NMR(300 MHz, CDCl₃) 1.09 (2H, m), 2.41 (2H, t, J=7.5 Hz), 3.05 (3H,s), 3.83 (2H, t, J=7 Hz), 7.09 (2H, m), 8.05 (1H, s).

Mass spectrum: (M+1)=255

EXAMPLE 20 1-(3'-methanalphenyl)-2H-tetrahydropyridazin-3-one (FormulaII, R₁ =3-methanalphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 3-aminobenzaldehyde instead of3-aminobenzonitrile as R₁ -NH₂.

mp 113° C.

¹ H NMR(300 MHz, CDCl₃) 1.97-2.08 (2H, m), 2.43 (2H, t, J=7.8 Hz), 3.80(2H, t, J=6.6 Hz), 7.25-7.33 (1H, m), 7.45-7.53 (3H, m), 7.84 (1H, brs), 9.99 (1H, s).

Mass spectrum: M+=204

EXAMPLE 21 1-(5-indanyl)-2H-tetrahydropyridazin-3-one (Formula II, R₁=5-indanyl ; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using aminoindane instead of3-aminobenzonitrile as R₁ -NH₂.

¹ H NMR(300 MHz, CDCl₃) 1.9 (2H, m), 2.1 (2H, m), 2.45 (2H, t), 2.85(4H, m), 3.65 (2H, t), 6.7-7.2 (3H, m), 7.5 (1H, br s).

Mass spectrum: M+=216

EXAMPLE 22 1-(5-tetrahydronaphthyl)-2H-tetrahydropyridazin-3-one(Formula II, R₁ =5-tetrahydronaphthyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using aminotetrahydronaphthylene insteadof 3-aminobenzonitrile as R₁ -NH₂.

mp 153° C.

¹ H NMR(300 MHz, CDCl₃) 1.72-1.90 (6H, m), 2.60 (2H, t, J=7.2 Hz),2.63-2.71 (2H, m), 2.77-2.85 (2H, m), 3.31-3.38 (2H, m), 6.90 (1H, d,J=7.5 Hz), 6.9- (1H, d, J=7.5 Hz), 7.11 (1H, t, J=7.5 Hz), 7.20 (1H, brs).

Mass spectrum: M+=230

EXAMPLE 23 1-(3-dibenzofuranyl)-2H-tetrahydropyridazin-3-one (FormulaII, R₁ =3-dibenzofuranyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using aminodibenzofuran instead of3-aminobenzonitrile as R₁ -NH₂.

mp 149° C.

¹ H NMR(300 MHz, CDCl₃) 2.02 (2H, m), 2.48 (2H, t, J=7.5 Hz), 3.82 (2H,t, J=6.5 Hz), 7.03 (1H, dd, J=8.5, 2.2 Hz), 7.22 (1H, d, J=2.2 Hz), 7.32(1Hz, ddd, J=7.7, 7.4, 1.1Hz), 7.39 (1H, br s), 7.40 (1H, ddd, J=8.17.4, 1.5 Hz)7.53 (1H, d, J=7.7 Hz), 7.85 (1H, d, J=8.5 Hz), 7.87 (1H,m).

Mass spectrum: M+=266

EXAMPLE 24 1-(3',5'-dimethylphenyl)-2H-tetrahydropyridazin-3-one(Formula II, R₁ =3,5-dimethylphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 2,6-dimethylaniline instead of3-aminobenzonitrile as R₁ -NH₂.

mp 146° C.

¹ H NMR(300 MHz, CDCl₃) 1.94 (2H, m), 2.29 (6H, s), 2.44 (2H, t, J=7Hz), 3.69 (2H, t, J=6 Hz), 6.63 (3H, s), 7.29 (1H, br s).

Mass spectrum: M+=204

EXAMPLE 25 1-(2',6'-dimethylphenyl)-2H-tetrahydropyridazin-3-one(Formula II, R₁ =2,6-dimethylphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 3,5-dimethylaniline instead of3-aminobenzonitrile as R₁ -NH₂.

¹ H NMR(300 MHz, CDCl₃) 2.02 (2H, m), 2.35 (6H, s), 2.56 (2H, t, J=6.5Hz), 3.32 (2H, m), 7.01 (3H, s), 7.55 (1H, br s).

Mass spectrum: M+=204

EXAMPLE 26 1-(3',5'-dichlorophenyl)-2H-tetrahydropyridazin-3-one(Formula II, R₁ =3,5-dichlorophenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 3,5-dichloroaniline instead of3-aminobenzonitrile as R₁ -NH₂.

¹ H NMR(300 MHz, CDCl₃) 2.05 (2H, m), 2.42 (2H, t, J=7 Hz), 3.70 (2H,t,J=6.5 Hz), 6.88 (2H, m), 6.94 (1H, m), 7.43 (1H, br s).

Mass spectrum: M+=245

EXAMPLE 27 1-(2',3'-difluorophenyl)-2H-tetrahydropyridazin-3-one(Formula II, R₁ =2,3-difluorophenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 2,3-difluoroaniline instead of3-aminobenzonitrile as R₁ -NH₂.

mp 170° C.

¹ H NMR(300 MHz, CDCl₃) 1.90 (2H, m), 2.54 (2H, t), 3.67 (2H, t),6.83-7.08 (3H, m), 7.50 (1H, br s).

Mass spectrum: M+=212

Anal.Calc'd. for C₁₀ H₁₀ F₂ N₂ O : C, 56.60; H, 4.75; N, 13.20.

Found : C, 55.55; H, 4.71; N, 13.42

EXAMPLE 28 1-(2',6'-difluorophenyl)-2H-tetrahydropyridazin-3-one(Formula II, R₁ =2,6-difluorophenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 2,6-difluoroaniline instead of3-aminobenzonitrile as R₁ -NH₂.

mp 156° C.

¹ H NMR(300 MHz, CDCl₃) 2.0 (2H, m), 2.62 (2H, t), 3.47 (2H, t), 6.88(2H, m), 7.03-7.13 (1H, m), 7.60 (1H, br s).

Mass spectrum: M+=212

Anal Calc'd. for C₁₀ H₁₀ F₂ N₂ O : C, 56.60; H, 4.75; N, 13.20.

Found : C, 56.45; H, 4.80; N, 13.13

EXAMPLE 29 1-(2',5'-difluorophenyl)-2H-tetrahydropyridazin-3-one(Formula II, R₁ =2,5-difluorophenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 2,5-difluoroaniline instead of3-aminobenzonitrile as R₁ -NH₂.

mp 169° C.

¹ H NMR(300 MHz, CDCl₃) 1.85 (2H, m), 2.54 (2H, t), 3.64-3.70 (2H, m),6.65-6.75 (1H, m), 6.85-6.93 (2H, m), 6.97-7.07 (2H, m), 7.83 (1H, brs).

Mass spectrum: (M+1)=213

Anal.Calc'd for C₁₀ H₁₀ F₂ N₂ O : C, 56.60; H, 4.75; N, 13.20.

Found : C, 56.45; H, 4.80; N, 13.13

EXAMPLE 30 1-(3',5'-difluorophenyl)-2H-tetrahydropyridazin-3-one(Formula II, R₁ =3,5-difluorophenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 3,5-difluoroaniline instead of3-aminobenzonitrile as R₁ -NH₂.

mp 128° C.

¹ H NMR(300 MHz, CDCl₃) 2.0 (2H, m), 2.41 (2H, t), 3.70 (2H, t), 6.38(1H, m), 6.51 (2H, m), 7.50 (1H, br s).

Mass spectrum: M+=212

Anal.Calc'd for C₁₀ H₁₀ F₂ N₂ O : C, 56.60; H, 4.75; N, 13.20.

Found : C, 56.58; H, 4.72; N, 13.10

EXAMPLE 311-(4'-fluoro-3'-trifluoromethylphenyl)-2H-tetrahydropyridazin-3-one(Formula II, R₁ =4-fluoro-3-trifluoromethylphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 4-fluoro-3-trifluoromethylanilineinstead of 3-aminobenzonitrile as R₁ -NH₂.

mp 143° C.

¹ H NMR(300 MHz, CDCl₃) 1.99 (2H, m), 2.46 (2H, t), 3.72 (2H, t),7.1-7.25 (3H, m), 8.04 (1H, br s.).

Mass spectrum: M+=262

Anal.Calc'd. for C₁₁ H₁₀ F₄ N₂ O : C, 50.39; H, 3.84; N, 10.68.

Found : C, 50.45; H, 3.87; N, 10.54

EXAMPLE 321-(3',5'-bis-trifluoromethylphenyl)-2H-tetrahydropyridazin-3-one(Formula II, R₁ =3,5-bis-trifluoromethylphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 3,5-bis-trifluoromethylanilineinstead of 3-aminobenzonitrile as R₁ -NH₂.

mp 145° C.

¹ H NMR(300 MHz, CDCl₃) 2.05 (2H, m), 2.45 (2H, t, J=7.5 Hz), 3.83 (2H,t, J=6.3 Hz), 7.36-7.47 (3H, m), 8.10 (1H, br s).

Mass spectrum: M+=312

Anal.Calc'd for C₁₂ H₁₀ F₆ N₂ O : C, 46.16; H, 3.73; N, 8.97.

Found : C, 46.24; H, 3.27; N, 8.75

EXAMPLE 33 1-(4'-bromo-3'-methylphenyl)-2H-tetrahydropyridazin-3-one(Formula II, R₁ =4-bromo-3-methylphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 4-bromo-3-methylaniline instead of3-aminobenzonitrile as R₁ -NH₂.

mp 154° C.

¹ H NMR(300 MHz, CDCl₃) 1.96 (2H, m), 2.37 (3H, s), 2.42 (2H, t, J=7.5Hz), 3.68 (2H, t, J=6.8 Hz), 6.70 (1H, dd, J=8.7,3.3 Hz) 6.87 (1H, d,J=3.3 Hz), 7.41 (1H, d, J=8.7 Hz), 7.78 (1H, br s).

Mass spectrum: M+=269

EXAMPLE 341-(4'-(2-diethylaminoethyl)carboxylphenyl)-2H-tetrahydropyridazin-3-one(Formula II, R₁ =4-(2-diethylaminoethyl)-carboxylphenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 4-(2-diethylaminoethyl)carboxylaniline instead of 3-aminobenzonitrile as R₁ -NH₂.

mp 166° C.

¹ H NMR(60 MHz, DMSOd₆) 1.0 (6H, t, J=7 Hz), 1.90-2.10 (2H, m), 2.35(2H, t, J=7 Hz), 2.45 (2H, t, J=7 Hz), 2.50 (2H, t, J=7 Hz) 2.70 (4H, q,J=7 Hz), 3.70 (2H, t, J=7 Hz), 6.85-6.95 (2H, m), 7.25-7.35 (2H, m),7.55 (1H, br s).

Mass spectrum: M+=319

EXAMPLE 35 1-(3,4,5-trichlorophenyl)-2H-tetrahydropyridazin-3-one(Formula II, R₁ =3,4,5-trichlorophenyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using 3,4,5-trichloroaniline instead of3-aminobenzonitrile as R₁ -NH₂.

mp 199° C.

¹ H NMR(60 MHz, DMSOd₆) 1.85-1.95 (2H, m), 2.52 (2H, t, J=7 Hz), 3.68(2H, t, J=7 Hz), 6.78 (2H, s), 7.50 (1H, br s).

Mass spectrum: M+=279

EXAMPLE 36 1-(N-ethyl-3-dibenzopyrolyl)-2H-tetrahydropyridazin-3-one(Formula II, R₁ =N-ethyl-3-dibenzopyrolyl; R₂ =H)

The title compound was prepared according to the method of Scheme I asdescribed for Example 1, except using N-ethyl-3-aminodibenzopyroleinstead of 3-aminobenzonitrile as R₁ -NH₂.

mp 182° C.

¹ H NMR (60 MHz, DMSOd₆) 1.22 (3H, t, J=7 Hz), 1.85-1.95 (2H, m), 2.47(2H, t, J=7 Hz), 3.75 (2H, t, J=7 Hz), 4.30 (2H, q, J=7 Hz), 6.87-7.00(2H, m), 7.05-7.55 (5H, m), 7.60 (1H, br s).

Mass spectrum: M+=293

The following compounds presented in Table 1 may be prepared using themethods according to Scheme I in an analogous manner as Example 1.

                  TABLE 1                                                         ______________________________________                                        Formula II Compounds                                                          ______________________________________                                        1-(3-cyano-4-phenoxyphenyl)-2H-tetrahydro-                                    pyridazin-3-one                                                               (Formula II, R.sub.1 = 3-cyano-4-phenoxyphenyl, R.sub.2 = H)                  1-(3,5-dicyanophenyl)-2H-tetrahydropyridazin-3-one                            Formula II, R.sub.1 = 3,5-dicyanophenyl, R.sub.2 = H                          1-(3-cyano-5-ethylphenyl)-2H-tetrahydropyridazin-3-one                        Formula II, R.sub.1 = 3-cyano-5-ethylphenyl, R.sub.2 = H                      1-(3-cyano-5-isobutylphenyl)-2H-tetrahydro-                                   pyridazin-3-one                                                               Formula II, R.sub.1 = 3-cyano-5-isobutylphenyl, R.sub.2 = H                   1-(3-cyano-5-dodecylphenyl)-2H-tetrahydro-                                    pyridazin-3-one                                                               Formula II, R.sub.1 = 3-cyano-5-dodecylphenyl, R.sub.2 = H                    1-(3-cyano-5-chlorophenyl)-2H-tetrahydropyridazin-3-one                       Formula II, R.sub.1 = 3-cyano-5-chlorophenyl, R.sub.2 = H                     1-(3-cyano-5-fluorophenyl)-2H-tetrahydropyridazin-3-one                       Formula II, R.sub.1 = 3-cyano-5-fluorophenyl, R.sub.2 = H                     1-(3-methylmercaptophenyl)-2H-tetrahydropyridazin-3-one                       Formula II, R.sub.1 = 3-methylmercaptophenyl, R.sub.2 = H                     1-(4-benzylphenyl)-2H-tetrahydropyridazin-3-one                               Formula II, R.sub.1 = 4-benzylphenyl, R.sub.2 = H                             1-(2-(7-bromofluorenyl))-2H-tetrahydropyridazin-3-one                          ##STR6##                                                                     1-(6-(3,4-benzocoumarinyl))-2H-tetrahydro-                                    pyridazin-3-one                                                                ##STR7##                                                                     1-(3-(9-fluorenonyl))-2H-tetrahydropyridazin-3-one                             ##STR8##                                                                     1-(5-(2-methoxypyridyl))-2H-tetrahydropyridazin-3-one                          ##STR9##                                                                     1-(4-morpholinophenyl)-2H-tetrahydropyridazin-3-one                            ##STR10##                                                                    1-(5-thianaphthyl)-2H-tetrahydropyridazin-3-one                                ##STR11##                                                                    1-(5-benzofuranyl)-2H-tetrahydropyridazin-3-one                                ##STR12##                                                                    1-(4-(2,1,3-benzothiadiazole))-2H-tetrahydro-                                 pyridazin-3-one                                                                ##STR13##                                                                    1-(2-(4,6-dimethylpyrimidyl))-2H-tetrahydro-                                  pyridazin-3-one                                                                ##STR14##                                                                    1-(2-(4,6-dimethylpyridyl))-2H-tetrahydro-                                    pyridazin-3-one                                                                ##STR15##                                                                    1-(2-(5-ethyl-1,3,4-thiadiazole))-2H-tetrahydro-                              pyridazin-3-one                                                                ##STR16##                                                                    1-(2-(5-trifluoromethyl-1,3,4-thiadiazole))-2H-                               tetrahydropyridazin-3-one                                                      ##STR17##                                                                    ______________________________________                                    

EXAMPLE 37 1-(3'-cyanophenyl)-4-methyl-2H-tetrahydropyridazin-3-oneFormula II, R₁ =3'-cyanophenyl; R₂ =4-methyl

The title compound can be prepared according to Scheme I in an analogousmanner using the methods described for Example 1, substituting ethyl4-bromo-2-methyl-butyrate for ethyl 4-bromobutyrate.

mp 147° C.

¹ H NMR(300 MHz, CDCl₃) 1.17 (3H, d), 1.66 (1H, m), 2.37 (2H, ml), 3.64(1H, m), 3.90 (1H, m), 7.18-7.25 (3H, m), 7.35-7.43 (1H, m), 7.67 (1H,br s).

Mass spectrum: M+=215

Anal.Calc'd. for C₁₂ H₁₃ N₃ O : C, 66.96; H, 6.09; N, 19.52.

Found : C, 67.17; H, 6.17; N, 18.83

EXAMPLE 38 1-phenyl-4-butyl-2H-tetrahydropyridazin-3-one Formula II, R₁=phenyl; R₂, =4-butyl.

The title compound can be prepared in a manner analogous to Example 1,substituting ethyl-4-bromo-2-butyl-butyrate forethyl-4-bromo-2-butyl-butyrate for ethyl-4-bromobutyrate, and anilinefor 3-aminobenzonitrile.

Mass spectrum: M+=232

EXAMPLE 39 1-phenyl-4-benzyl-2H-tetrahydropyridazin-3-one Formula II, R₁=phenyl; R₂, =4-benzyl.

The title compound can be prepared in a manner analogous to Example 1,substituting ethyl 4-bromo-2-benzyl-butyrate for ethyl-4-bromobutyrateand aniline for 3-aminobenzonitrile.

¹ H NMR(300 MHz, CDCl₃) 1.65 (1H, m), 1.88 (1H, m), 2.70 (2H, m), 3.30(1H, m), 3.65 (2H, m), 6.95 (2H), 7.25 (9H).

Mass spectrum: M+=266

EXAMPLE 40 1-phenyl-5-butyl-2H-tetrahydropyridazin-3-one Formula II, R₁=phenyl; R₂, =5-butyl.

The title compound can be prepared in a manner analogous to Example 1,substituting ethyl 3-butyl-4-bromobutyrate for ethyl-4-bromobutyrate andaniline for 3-aminobenzonitrile.

Mass spectrum: M+=232

EXAMPLE 41 1-(4'-phenoxyphenyl)-4-methyl-2H-tetrahydropyridazin-3-oneFormula II, R₁ =4'-phenoxyphenyl; R₂ =4-methyl.

The title compound can be prepared in a manner analogous to Example 1,substituting 4-phenoxyaniline instead of 3-aminobenzonitrile andethyl-2-methyl-4-bromobutyrate for ethyl-4-bromobutyrate.

mp 128° C.

¹ H NMR(300 MHz, CDCl₃) 1.21 (3H, d), 1.56-1.70 (1H, m), 2.16-2.29 (1H,m), 2.41-2.56 (1H, m), 3.55-3.67 (1H, m), 3.74-3.85 (1H, m), 6.93-7.11(7H, m), 7.28-7.40 (3H, m).

Mass spectrum: M+=282

The following compounds shown in Table 2 may be prepared according tothe method of Scheme I in an analogous manner as Example 1, substitutingthe appropriately substituted ethyl 4-bromobutyrate and primary amine R₁-NH₂ for ethyl 4-bromobutyrate and 3-aminobenzonitrile respectively.

                  TABLE 2                                                         ______________________________________                                        Formula II Compounds                                                          ______________________________________                                        1-(3'-cyanophenyl)-4-ethyl-2H-tetrahydropyridazin-3-one                       Formula II, R.sub.1 = 3-cyanophenyl, R.sub.2 = 4-ethyl                        1-(3'-cyanophenyl)-4-isobutyl-2H-tetrahydropyridazin-3-                       one                                                                           Formula II, R.sub.1 = 3-cyanophenyl, R.sub.2 = 4-isobutyl                     1-(3'-cyanophenyl)-4-butyl-2H-tetrahydropyridazin-3-one                       Formula II, R.sub.1 = 3-cyanophenyl, R.sub.2 = 4-butyl                        1-(3'-cyanophenyl)-4-benzyl-2H-tetrahydro-                                    pyridazin-3-one                                                               Formula II, R.sub.1 = 3-cyanophenyl, R.sub.2 = 4-benzyl                       1-(3'-cyanophenyl)-4-phenyl-2H-tetrahydro-                                    pyridazin-3-one                                                               Formula II, R.sub.1 = 3-cyanophenyl, R.sub.2 = 4-phenyl                       1-(3'-cyanophenyl)-4-methoxy-2H-tetrahydro-                                   pyridazin-3-one                                                               Formula II, R.sub.1 = 3-cyanophenyl, R.sub.2 = 4-methoxy                      1-(3'-cyanophenyl)-4,5-dimethyl-2H-tetrahydro-                                pyridazin-3-one                                                               Formula II, R.sub.1 = 3-cyanophenyl, R.sub.2 = 4,5-dimethyl                   1-(3'-cyanophenyl)-4-(3-oxobutyl)-2H-tetrahydro-                              pyridazin-3-one                                                               Formula II, R.sub.1 = 3-cyanophenyl, R.sub.2 = oxobutyl                       1-(3'-cyanophenyl)-4-(3-hydroxybutyl)-2H-tetrahydro-                          pyridazin-3-one                                                               Formula II, R.sub.1 = 3-cyanophenyl, R.sub.2 = 3-hydroxybutyl                 1-(3'-cyanophenyl)-4-(2-diethylaminoethyl)-2H-                                tetrahydropyridazin-3-one                                                     Formula II, R.sub.1 = 3-cyanophenyl, R.sub.2 = 2-diethyl-                     aminoethyl                                                                    1-(3'-cyanophenyl)-5-thiophenyl-2H-tetrahydro-                                pyridazin-3-one                                                               Formula II, R.sub.1 = 3-cyanophenyl, R.sub.2 = thiophenyl                     1-(3'-cyanophenyl)-5-thioethyl-2H-tetrahydro-                                 pyridazin-3-one                                                               Formula II, R.sub.1 = 3-cyanophenyl, R.sub.2 = thioethyl                      1-(3'-cyanophenyl)-5-cyano-2H-tetrahydropyridazin-3-one                       Formula II, R.sub.1 = 3-cyanophenyl, R.sub.2 = cyano                          1-(3'-cyanophenyl)-5-dimethylamino-2H-tetrahydro-                             pyridazin-3-one                                                               Formula II, R.sub.1 = 3-cyanophenyl, R.sub.2 = dimethylamino                  1-(3'-cyanophenyl)-4,5-dihydroxy-2H-tetrahydro-                               pyridazin-3-one                                                               Formula II, R.sub.1 = 3-cyanophenyl, R.sub.2 = 4,5-dihydroxy                  1-phenyl-4-dodecyl-2H-tetrahydropyridazin-3-one                               Formula II, R.sub.1 = phenyl, R.sub.2 = dodecyl                               1-phenyl-5-phenoxy-2H-tetrahydropyridazin-3-one                               Formula II, R.sub.1 = phenyl, R.sub.2 = 5-phenoxy                             1-phenyl-4-butoxy-2H-tetrahydropyridazin-3-one                                Formula II, R.sub.1 = phenyl, R.sub.2 = 4-butoxy                              ______________________________________                                    

b) Scheme II

Certain pyridazinone compounds of this invention (e.g. the compounds ofExamples 42-44) are preferably made according to Scheme II below.Reaction of a hydrazine (6) or a hydrazine salt with acetic anhydride inthe presence of an appropriate base yields the corresponding acetylanhydride (7). Condensation of (7) with an appropriately substitutedethylbromobutyrate (8) using diisopropylethylamine produces thedisubstituted hydrazine (9). The hydrazine (9) is treated with asuitable base to effect intramolecular cyclization to the pyridazinonestructure Formula II. ##STR18##

Further details of this scheme are provided in the following examples.

EXAMPLE 42 3-methylphenyl-2H-tetrahydropyridazin-3-one Formula II, R₁=3-methylphenyl; R₂ =H

a) Acetyl 3-methylphenylhydrazide

Meta-tolylhydrazine hydrochloride salt (20 g, 0.13 mole) was dissolvedin 1N NaOH (250 mL) and tetrahydrofuran (60 mL). With stirring, aceticanhydride (13 g, 0.13 mL) was added dropwise, and after stirring for 30min the mixture was extracted with ether (3×100 mL). The combined etherextract was evaporated to afford a solid residue.

Recrystallization from a mixture of pentane and dichloromethane (1:1)gave the hydrazide (18.0 g), mp 101°-103° C.

b) Ethyl 4-(2-(acetyl 3-methylphenyl hydrazine)) butyrate

A mixture of hydrazide from part a (17.0 g, 0.1 mole),diisopropylethylamine (14.2 g, 0.11 mole) and ethyl 4-bromobutyrate(21.5 g, 0.11 mole) in toluene (100 mL) was refluxed under nitrogen forthree days. The mixture was allowed to cool after which water (75 mL)and dichloromethane:ether (1:1, 100 mL) was added. The organic layer wasseparated, washed with water (65 mL), dried over MgSO₄, filtered andevaporated to give a residue (34.4 g).

c) 3-Methylphenyl-2H-tetrahydropyridazin-3-one.

The residue from part b (34.4 g) was dissolved in dry ethanol (100 mL)and with stirring under nitrogen, sodium (2.3 g, 0.1 mole) was added insmall portions and the mixture was refluxed for 15 h. The mixture wasallowed to cool and water (60 mL) was added. The mixture wasconcentrated in vacuo and the residue was partitioned in a mixture ofwater (50 mL) and dichloromethane (100 mL). The organic extract wasdried over MgSO₄, filtered and evaporated to give a solid residue (18.6g). Recrystallization from benzene gave the desired product (4.8 g,25%),

mp 114°-115° C. NMR (300 MHz, CDCl₃) 1.95(2 H, m), 2.34 (3 H, s), 2.43(2H, t, J=7.5 Hz), 3.70 (2 H, t, J--7.5 Hz), 6.75-6.85 (3 H, m), 7.19 (1H, m), 7.42 (1 H, br s).

EXAMPLE 43 1-(2'-methylphenyl)-2H-tetrahydropyridazin-3-one Formula II,R₁ =2-methylphenyl; R₂, Z=H

The title compound was prepared according to Scheme II in a manneranalogous to Example 42 except ortho-tolylhydrazine hydrochloride saltwas used instead of the meta-analog.

mp 169° C.

¹ H NMR (300 MHz, CDCl₃) 1.85 (2H, m), 2.32 (3H, s), 2.61 (2H, t, J=7Hz), 3.38 (2H, m), 7.0-7.2 (5H, m)

Mass spectrum: M+=190

EXAMPLE 44 1-(4'-methylphenyl)-2H-tetrahydropyridazin-3-one Formula II,R₁ =4-methylphenyl; R₂, Z=H

The title compound was prepared according to Scheme II in a manneranalogous to Example 42 except para-tolylhydrazine hydrochloride saltwas used instead of the meta-analog.

mp 131° C.

¹ H NMR (300 MHz, CDCl₃) 1.93 (2H, m), 2.30 (3H, s), 2.43 (2H, t, J=7Hz), 3.68 (2H, t, J=7 Hz), 6.92 (2H, m), 7.10 (2H, m), 7.55 (1H, br s).

Mass spectrum: M+=190

EXAMPLE 45 1-(2'-chlorophenyl)-2H-tetrahydropyridazin-3-one Formula II,R₁ =2-chlorophenyl; R₂ =H)

The title compound was prepared according to Scheme II in a manneranalogous to Example 42 except ortho-chlorophenylhydrazine hydrochloridesalt was used instead of the meta-tolylhydrazine hydrochloride salt.

mp 191° C.

¹ H NMR (300 MHz, CDCl₃) 1.85 (2H, m), 2.60 (2H, t, J=7 Hz), 3.65 (2H,m), 7.08 (1H, m), 7.23 (2H, m), 7.38 (1H, m), 8.28 (1H, br s).

Mass spectrum: M+=210

EXAMPLE 46 1-(3'-chlorophenyl)-2H-tetrahydropyridazin-3-one Formula II,R₁ =3-chlorophenyl; R₂ =H

The title compound was prepared according to Scheme II in a manneranalogous to Example 42 except meta-chlorophenylhydrazine hydrochloridesalt was used instead of the meta-tolylhydrazine hydrochloride salt.

mp 114° C.

¹ H NMR (300 MHz, CDCl₃) 2.02 (2H, m), 2.42 (2H, t, J=7 Hz), 3.70 (2H,t, J=7 Hz), 6.90 (2H, m), 7.0 (1H, t, J=2 Hz), 7.25 (1H, t, J=7 Hz),7.65 (1H, br s).

Mass spectrum: M+=210

EXAMPLE 47 1-(4'-chlorophenyl)-2H-tetrahydropyridazin-3-one Formula II,R₁ =4-chlorophenyl; R₂ =H

The title compound was prepared according to Scheme II in a manneranalogous to Example 42 except para-chlorophenylhydrazine hydrochloridesalt was used instead of the meta-tolylhydrazine hydrochloride salt.

mp 138° C.

¹ H NMR (300 MHz, CDCl₃) 1.98 (2H, m), 2.45 (2H, t, J=7 Hz), 3.70 (2H,t, J=7 Hz), 6.95 (2H, m), 7.27 (2H, m), 7.55 (1H, br s).

Mass spectrum: M+=210

EXAMPLE 50 1-(3'-bromophenyl)-2H-tetrahydropyridazin-3-one Formula II,R₁ =3-bromophenyl; R₂ =H

The title compound was prepared according to Scheme II in a manneranalogous to Example 42 except meta-bromophenylhydrazine hydrochloridesalt was used instead of the meta-tolylhydrazine hydrochloride salt.

mp 123° C.

¹ H NMR (300 MHz, CDCl₃) 2.00 (2H, m), 2.42 (2H, t, J=7 Hz), 3.70 (2H,t, J=7 Hz), 6.93 (1H, m), 7.05-7.2 (3H, m), 7.54 (1H, br s).

Mass spectrum: M+=256, 254

EXAMPLE 51 1-(2'-fluorophenyl)-2H-tetrahydropyridazin-3-one Formula II,R₁ =2-fluorophenyl; R₂ =H

The title compound was prepared according to Scheme II in a manneranalogous to Example 42 except ortho-fluorophenylhydrazine hydrochloridesalt was used instead of the meta-tolylhydrazine hydrochloride salt.

¹ H NMR (300 MHz, CDCl₃) 1.88 (2H, m), 2.55 (2H, t, J=7 Hz), 3.65 (2H,t, J=7 Hz), 7.05-7.15 (4H, m), 7.35 (1H, s).

Mass spectrum: M+=194

EXAMPLE 52 1-(3'-fluorophenyl)-2H-tetrahydropyridazin-3-one Formula II,R₁ =3-fluorophenyl; R₂ =H)

The title compound was prepared according to Scheme II in a manneranalogous to Example 42 except meta-fluorophenylhydrazine hydrochloridesalt was used instead of the meta-tolylhydrazine hydrochloride salt.

mp 131° C.

¹ H NMR (300 MHz, CDCl₃) 2.00 (2H, m), 2.42 (2H, t, J=7 Hz), 3.72 (2H,t, J=7 Hz), 6.70 (3H, m), 7.25 (1H, m), 7.55 (1H, br s).

Mass spectrum: M+=194

EXAMPLE 53 1-(4'-fluorophenyl)-2H-tetrahydropyridazin-3-one Formula II,R₁ =4-fluorophenyl; R₂ =H

The title compound was prepared according to Scheme II in a manneranalogous to Example 42 except para-fluorophenylhydrazine hydrochloridesalt was used instead of the meta-tolylhydrazine hydrochloride salt.

mp 148° C.

¹ H NMR (300 MHz, CDCl₃) 1.92 (2H, m), 2.45 (2H, t, J=7 Hz), 3.65 (2H,t, J=7 Hz), 7.0 (4H, m), 7.55 (1H, br s).

Mass spectrum: M+=194

The methods of Scheme II can be applied to substituted ethylbromobutyrates (8) as exemplified by the following example.

EXAMPLE 54 1-phenyl-5-methyl-2H-tetrahydropyridazin-3-one Formula II,R1=phenyl, R2=5-methyl

The title compound was prepared according to Scheme II, where part adescribes the synthesis of a substituted bromobutyrate (8). Condensationof (8) with acetyl phenylhydrazide provided the correspondingintermediate (9) which was reduced by catalytic hydrogenation and thentreated with base to effect cyclization to the pyridazinone structureII.

a) To a solution of ethyl 3-methyl-2-butenoate (26 g, 0.2 mole) intetrachloromethane (200 mL) was added N-bromosuccinimide (0.2 mole) andbenzoyl peroxide (0.1 g), and the mixture was heated at reflux under anitrogen atmosphere for 3 hours. The mixture was allowed to cool to roomtemperature. Water (100 mL). was added, and the organic layer wasseparated, washed with aqueous saturated NaCl, dried over MgSO₄,filtered and evaporated to provide a residue (38 g).

b) The residue from part a (20 g, 0.1 mole) was added to a solution ofacetyl phenylhydrazide (15 g, 0.1 mole), diisopropylethylamine (0.1mole) in benzene (200 mL) and heated at reflux for 3 days. The mixturewas allowed to cool to room temperature. Water (100 mL) was added, andthe organic layer was separated, washed with aqueous saturated NaCl,dried over MgSO₄, filtered and evaporated to provide a solid residue,which was washed with ether (2×10 mL) to give a pale yellow solid (10g).

c) A solution of intermediate from part b (5.4 g, 0.02 mole) in ethanol(100 mL) was stirred with PtO₂ (0.4 g) under a hydrogen atmosphere for 3hours. The mixture was filtered and evaporated to provide a residue (5.5g).

d) To a solution of sodium (0.025 mole) in ethanol (50 mL) was added theresidue from part c (5.5 g) and the mixture was refluxed under nitrogenfor 16 hours. The mixture was allowed to cool at room temperature, water(50 mL) was added, and 1N HCl was added to adjust the solution to pH 7.The mixture was concentrated by evaporating the ethanol and thenextracted with dichloromethane (2×50 mL). The organic extract was driedover MgSO₄, filtered and evaporated to provide a residue. Purificationby column chromatography (silica gel, 10% ethylacetate indichloromethane) gave the desired product (1.1 g), mp 132.

¹ H NMR (300 MHz, CDCl₃) 0.97 (3H, d, J=6.5 Hz), 2.08 (1H, dd, J=14,8Hz), 2.27 (1H, m), 2.56 (1H, dd, J=15,7 Hz), 3.17 (1H, dd, J=12, 10 Hz),3.89 (1H, dd, J=13, 5 Hz), 6.98 (3H, m), 7.29 (2H, m), 7.37 (1H, br s).

Mass spectrum: M+=190

Scheme III

Certain pyridazinone compounds of this invention (e.g. those in Example55-58) of Formula III can be prepared by Scheme III below. 1H,2H-pentahydropyridazin-3-one (10) is prepared according to the procedureoutlined in Gut, et al, Coll. Czech Chem. Commun. 1968 Vol. 33 p 2087.The pyridazinone (10) is condensed with an appropriate electrophylicunit R1 - X (11) (where X is a leaving group such as a halogen) in thepresence of an appropriate base or catalyst to yield the pyridazinoneIII. ##STR19##

EXAMPLE 55 1-(2-benzoxazole)-2H-tetrahydropyridazin-3-one Formula III,R₁ =2-benzoxazole; R₂ =H

To a stirred mixture of 1H,2H-pentahydropyridazin-3-one (549 mg, 5.48mmol) and tetra-n-butylammonium bromide (catalytic amount) intetrahydrofuran (0.5 mL) was added 2-chlorobenzoxazole (1.0 mL) andtoluene (5 mL). Aqueous 20% sodium hydroxide (0.5 ml) was added dropwiseto the mixture which was stirred at room temperature for four days. Theorganic layer was separated and evaporated to yield the desired product(217 mg), mp 141° C.

¹ H NMR (300 MHz, CDCl₃) 2.21 (2H, m), 2.52 (2H, t, J=7.0 Hz), 4.01 (2H,t, J=7.0 Hz), 7.22 (1H, m), 7.30 (1H, m), 7.38 (1H, d, J=8.0 Hz), 7.58(1H, d, 8.0 Hz), 8.6 (1H, br s).

Mass spectrum: M+=217.0842

EXAMPLE 56 1-(2-pyrimidyl)-2H-tetrahydropyridazin-3-one Formula III, R₁=2-pyrimidyl; R₂ =H

A stirred mixture of 1H,2H-pentahydropyridazin-3-one (200 mg, 2.0 mmol)and 2-chloropyrimidine (110 mg, 0.96 mmol) was heated at 80° C. undernitrogen for 24 hours. The melt was allowed to cool to room temperature,and purification by column chromotography (silica gel, hexane-ethylacetate gradient, 1:1 to 0.1:1) gave the desired product (20 mg), mp132.

¹ H NMR (300 MHz, CDCl₃) 2.08 (2H, m), 2.54 (2H, t, J=7.1 Hz), 4.07 (2H,t, J=6.7 Hz), 6.67 (1H, t, J=4.8 Hz), 8.39 (2H, d, J=4.8 Hz), 8.80 (1H,br s).

Mass spectrum: M+=178

EXAMPLE 57 1-(2-pyridyl)-2H-tetrahydropyridazin-3-one Formula III, R₁=2-pyridyl; R₂ =H

The title compound was prepared according to Scheme III in a manneranalogous to Example 56 except substituting 2-chloropyridine for2-chloropyrimidine and heating at 100° C.

¹ H NMR (300 MHz, CDCl₃) 2.10 (2H, m), 2.36 (2H, t, J=7.3 Hz), 4.01 (2H,t, J=6.6 Hz), 6.81 (1H, ddd, J=7.1, 4.9, 0.7 Hz), 6.92 (1H, dt, J=8.5,0.7 Hz), 7.59 (1H, ddd, J=8.5, 7.1, 1.8 Hz), 7.72 (1H, br s), 8.24 (1H,ddd, J=4.9, 1.8, 0.7 Hz).

Mass spectrum: M+=177

EXAMPLE 58 1-(2,4-dinitrophenyl)-2H-tetrahydropyridazin-3-one FormulaIII R₁ =2,4-dinitrophenyl; R₂, Z=H

The title compound was prepared according to Scheme III in a manneranalogous to Example 56 except substituting 1-fluoro-2,4-dinitrobenzenefor 2-chloropyrimidine and heating at 100° C.

mp 185° C. (dec)

¹ H NMR (300 MHz, CDCl₃) 2.19 (2H, m), 2.44 (2H, t, J=7.2 Hz), 3.68 (2H,t, J=7.0 Hz), 7.39 (1H, d, J=9.2 Hz), 7.69 (1H, br s), 8.35 (1H, dd,J=9.2, 2.6 Hz), 8.72 (1H, d, J=2.6 Hz).

Mass spectrum: M+=266

The following compounds may be prepared according to Scheme III, FormulaIII, in an analogous fashion as Example 56, heating 1H,2H-pentahydropyridazin-3-one with the corresponding electrophile (R'-X)with or without an appropriate solvent and base catalysis, as summarizedin Table 3.

                  TABLE 3                                                         ______________________________________                                        Formula III compounds                                                         ______________________________________                                        1-(2-benzothiazoyl)-2H-tetrahydropyridazin-3-one                               ##STR20##                                                                    1-(3,5-dinitropyridyl)-2H-tetrahydropyridazin-3-one                            ##STR21##                                                                    1-(2,5-dimethylpyrazyl)-2H-tetrahydropyridazin-3-one                           ##STR22##                                                                    1-(1,3-dimethyluracyl)-2H-tetrahydropyridazin-3-one                            ##STR23##                                                                    1-(5-nitrothiazolyl)-2H-tetrahydropyridazin-3-one                              ##STR24##                                                                    1-(4-methylquinolinyl)-2H-tetrahydropyridazin-3-one                            ##STR25##                                                                    1-(4-methyl-5-nitropyridyl)-2H-tetrahydro-                                    pyridazin-3-one                                                                ##STR26##                                                                    1-(3-nitropyridyl)-2H-tetrahydropyridazin-3-one                                ##STR27##                                                                    1-(2-quinolinyl)-2H-tetrahydropyridazin-3-one                                  ##STR28##                                                                    1-(1,3-dimethyl-2,6(1H, 3H)-purindionyl)-2H-                                  tetrahydropyridazin-3-one                                                      ##STR29##                                                                    ______________________________________                                    

d) Scheme IV

Certain pyridazinones of this invention (e.g. those of Examples 59-66)of the general Formula IV can be prepared by reaction Scheme IV. Apyridazinone (12) is made according to reaction Schemes I-III above withthe appropriate "R1" substitution. The pyridazinone (12) is treated withtwo equivalents of a strong base such as tert-butyllithium or acombination of potassium hydride and tert-butyllithium, followed bycondensation with an electrophile, R2-X (13) (for example when X ishalogen, carbonyl, acylchloride and the like), yields the 4-substitutedcompounds of Formula IV. ##STR30##

EXAMPLE 59 1-phenyl-4-(2-propenyl)-2H-tetrahydropyridazin-3-one FormulaIV, R₁ =phenyl; R₂ =allyl.

To a solution of 1-phenyl-2H-tetrahydropyridazin-3-one (1.76 g, 0.01mole) in tetrahydrofuran (50 mL) at 5° C. under nitrogen and withstirring was added a suspension of KH (0.015 mole) in tetrahydrofuran(10 mL). Gas evolution (H₂) occurred. After 15 minutes the mixture wascooled to -78° C. and tert-butyllithium (7.5 mL of 1.5 M solution inpentane) was added dropwise. After stirring 5 minutes, CuCN (0.45 g,0.005 mole) was added, and the mixture was allowed to warm to 5° C. for20 minutes after which 3-bromopropene (0.011 mole) was added. Themixture was stirred for 30 minutes at 5° C. then 10% aqueous ammoniumchloride (40 mL) and dichloromethane (50 mL) was added. The organiclayer was dried over MgSO4, filtered and evaporated to give a residue.Purification by column chromatography (silica gel, 30% ether indichloromethane) gave the desired product, mp 71° C.

¹ H NMR (300 MHz, CDCl₃) 1.64 (1H, m), 2.15 (2H, m), 2.43 (1H, m), 2.59(1H, m), 3.66 (1H, m), 3.81 (1H, m), 5.01 (2H, m), 5.73 (1H, m), 6.96(3H, m), 7.3 (2H, m), 7.5 (1H, br s).

Mass spectrum: M+=216

EXAMPLE 60 1-phenyl-4-(2-methyl-2-propenyl)-2H-tetrahydropyridazinoneFormula IV, R₁ =phenyl; R₂ =CH₂ C(CH₃)=CH₂

The title compound was prepared according to Scheme IV in a manneranalogous to Example 59 except 3-bromo-2-methylpropene was used insteadof 3-bromopropene.

mp 108° C.

¹ H NMR (300 MHz, CDCl₃) 1.57 (4H, m), 2.06 (2H, m), 2.55 (1H, m), 2.71(1H, dd, J=15, 4.5 Hz), 3.77 (2H, m), 4.62 (1H, m), 4.75 (1H, m), 6.98(3H, m), 7.21 (1H, br s), 7.30 (2H, m).

Mass spectrum: M+=230

EXAMPLE 61 1-phenyl-4-ethoxymethyl-2H-tetrahydropyridazinone Formula IV,R₁ =phenyl; R₂ =CH₂ OCH₂ CH₃.

The title compound was prepared according to Scheme IV in a manneranalogous to Example 59 except chloromethylethylether was used insteadof 3-bromopropene.

mp 83° C.

¹ H NMR (300 MHz, CDCl₃) 1.14 (3H, t, J=7.5 Hz), 1.80 (1H, m), 2.12 (1H,m), 3.46 (2H, q, J=7.5 Hz), 3.74 (4H, m), 7.0 (3H, m), 7.28 (3H, m).

Mass spectrum: M+=234

EXAMPLE 62 1-phenyl-4-benzyloxymethyl-2H-tetrahydropyridazinone FormulaIV, R₁ =phenyl; R₂ =CH₂ OCH₂ C₆ H₅.

The title compound was prepared according to Scheme IV in a manneranalogous to Example 59 except benzyl chloromethylether was used insteadof 3-bromopropene.

mp 86° C.

¹ H NMR (300 MHz, CDCl₃) 1.93 (1H, m), 2.13 (1H, m), 2.66 (1H, m), 3.75(4H, m), 4.49 (2H, q), 6.97 (3H, m), 7.26 (7H, m), 7.6 (1H, br s).

Mass spectrum: M+=296

EXAMPLE 63 1-phenyl-4-methylthiomethyl-2H-tetrahydropyridazinone FormulaIV, R₁ =phenyl; R₂ =CH₂ SCH₃.

The title compound was prepared according to Scheme IV in a manneranalogous to Example 59 except chloromethylmethylsulfide was usedinstead of 3-bromopropene.

mp 70° C.

¹ H NMR (300 MHz, CDCl₃) 1.80 (1H, m), 2.08 (3H, s), 2.30 (1H, m), 2.62(2H, m), 3.04 (1H, m), 3.77 (2H, m), 7.0 (3H, m), 7.28 (3H, m).

Mass spectrum: M+=236

EXAMPLE 64 1-phenyl-4-phenylthiomethyl-2H-tetrahydropyridazinone FormulaIV, R₁ =phenyl; R₂ =CH₂ SC₆ H₅

The title compound was prepared according to Scheme IV in a manneranalogous to Example 59 except chloromethylphenyl sulfide was usedinstead of 3-bromopropene.

¹ H NMR (300 MHz, CDCl₃) 1.80 (1H, m), 2.4 (1H, m), 2.63 (1H, m), 2.90(1H, dd, J=13, 3 Hz), 3.57 (1H, dd, J=13, 3 Hz), 3.67 (1H, m), 3.80 (1H,m), 6.97 (3H, m), 7.23 (8H, m).

Mass spectrum: M+=298

EXAMPLE 651-phenyl-4-(3-methyl-1-oxo-but-2-enyl)-2H-tetrahydropyridazin-3-oneFormula IV, R₁ =phenyl; R₂ =COCHC(CH₃)₂

The title compound was prepared according to Scheme IV in a manneranalogous to Example 59 except 3-methyl-but-2-enoyl chloride was usedinstead of 3-bromopropene.

mp 158° C.

¹ H NMR (300 MHz, CDCl₃) 1.86 (3H, s), 2.07 (3H, s), 2.45 (2H, m), 3.71(2H, m), 5.73 (1H, br s), 7.0 (5H, m), 7.3 (2H, m).

Mass spectrum: M+=258

EXAMPLE 66 1-phenyl-4-(hydroxymethylphenyl)-2H-tetrahydropyridazin-3-oneFormula IV, R₁ =phenyl; R₂ =CHOHC₆ H₅

The title compound was prepared according to Scheme IV in a manneranalogous to Example 59 except benzaldehyde was used instead of3-bromopropene.

¹ H NMR (300 MHz, CDCl₃) 1.50 (2H, m), 2.68 (1H, q), 3.56 (1H, m), 3.71(1H, m), 4.78 (1H, d), 5.00-5.50 (1H, br s), 6.92-7.05 (3H, m) 7.26-7.36(7H, m), 7.72 (1H, s).

Mass spectrum: M+=282

Anal.Calc'd. for C₁₇ H₁₈ N₂ O₂ : C, 72.32; H, 6.43; N, 9.92.

Anal. Found : C, 71.90; H, 6.40; N, 9.59.

Following the method used for Example 59, substituting 3-bromopropene asR₂ -X for an equivalent amount of an alternate electrophile R₂ -Xincluding halides, ketones, aldehydes, chloroformates, and acidchlorides, compounds of the Formula IV may be prepared as summarized inTable 4.

                  TABLE 4                                                         ______________________________________                                        Formula IV compounds                                                          ______________________________________                                        1-phenyl-4-ethyl-2H-tetrahydropyridazin-3-one                                 Formula IV, R.sub.1 = phenyl, R.sub.2 = CH.sub.2 CH.sub.3                     1-phenyl-4-hexyl-2H-tetrahydropyridazin-3-one                                 Formula IV, R.sub.1 = phenyl, R.sub.2 = (CH.sub.2).sub.5 CH.sub.3             1-(3'-ethylphenyl)-4-methoxymethyl-2H-tetrahydro-                             pyridazin-3-one                                                               Formula IV, R.sub.1 = 3-ethylphenyl, R.sub.2 = CH.sub.2 OCH.sub.3             1-(3'-ethylphenyl)-4-(2-hydroxyethyl)-2H-tetrahydro-                          pyridazin-3-one                                                               Formula IV, R.sub.1 = 3-ethylphenyl, R.sub.2 = CH.sub.2 CH.sub.2 OH           1-(3'-ethylphenyl)-4-(2-diethylaminoethyl)-2H-                                tetrahydropyridazin-3-one                                                     Formula IV, R.sub.1 = 3-ethylphenyl, R.sub.2 = CH.sub.2 CH.sub.2 N(CH.sub.    2 CH.sub.3).sub.2                                                             1-(3'-ethylphenyl)-4-benzoyl-2H-tetrahydro-                                   pyridazin-3-one                                                               Formula IV, R.sub.1 = 3-ethylphenyl, R.sub.2 = COC.sub.6 H.sub.5              1-(3'-ethylphenyl)-4-(1-hydroxyethyl)-2H-tetrahydro-                          pyridazin-3-one                                                               Formula IV, R.sub.1 = 3-ethylphenyl, R.sub.2 = CHOHCH.sub.3                   1-(3'-ethylphenyl)-4-(1-hydroxybutyl)-2H-tetrahydro-                          pyridazin-3-one                                                               Formula IV, R.sub.1 = 4-phenoxyphenyl, R.sub.2 = CHOH(CH.sub.2).sub.2         CH.sub.3                                                                      1-(4'-phenoxyphenyl)-4-propionyl-2H-tetrahydro-                               pyridazin-3-one                                                               Formula IV, R.sub.1 =  4-phenoxyphenyl, R.sub.2 = COCH.sub.2 CH.sub.3         1-(2-pyridyl)-4-butyl-2H-tetrahydropyridazin-3-one                            Formula IV, R.sub.1 = 2-pyridyl, R.sub.2 = (CH.sub.2).sub.3 CH.sub.3          1-(3'-methylphenyl)-4-methylcyano-2H-tetrahydro-                              pyridazin-3-one                                                               Formula IV, R.sub.1 = 3-methylphenyl, R.sub.2 = CH.sub.2 CN                   1-(3'-methylphenyl)-4-ethoxycarbonyl-2H-                                      tetrahydropyridazin-3-one                                                     Formula IV, R.sub.1 = 3-methylphenyl, R.sub.2 = COOCH.sub.2 CH.sub.3           ##STR31##                                                                     ##STR32##                                                                    1-phenyl-4-(1-hydroxy-2-methoxyethyl)-2H-tetrahydro-                          pyridazin-3-one                                                               Formula IV, R.sub.1 = phenyl, R.sub.2 = CHOHCH.sub.2 OCH.sub.3                 ##STR33##                                                                    ______________________________________                                    

II. Triazinone Synthesis a) Scheme V

Triazinone compounds of this invention of Formula V can be preparedaccording to general reaction Scheme V. Treatment of a substitutedbromoethylamine salt 14, such as hydrobromide, with ethyl-chloroformate(or an alternate alkyl or arylchloroformate, ClCO₂ R) in the presence ofan appropriate base, such as triethylamine, provides the bromocarbamateintermediate 15. The bromocarbamate 15 is condensed With an amine 1 inthe presence of an appropriate base to provide the carbamateintermediate 16. The intermediate 16 is then treated with sodium nitritein the presence of an acid to yield the N-nitroso intermediate 17, whichis reduced with zinc powder in the presence of acetic acid to providethe hydrazine intermediate 18. The hydrazine intermediate 18 is thencyclized with a suitable base such as ethylmagnesium bromide to providetriazinone compounds of Formula V. ##STR34##

A preferred embodiment of this reaction scheme is illustrated by thefollowing: ##STR35##

EXAMPLE 68 1-(phenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-one Formula V, R₁=phenyl, R₂ =R₄ =Z=H

a) To a suspension of bromoethylamine hydrobromide salt (255 g, 1.25mole) in dichloromethane (700 mL) was added triethylamine (252 g, 2.5mole) at 0° C. under nitrogen while stirring. A solution of ethylchloroformate (135.3 g, 1.25 mole) in dichloromethane (200 mL) was addedto the mixture dropwise maintaining the temperature of the reactionbetween 0°-4° C. After the addition, the mixture was stirred for onehour. Water (500 mL) was added, and the organic layer was separated,washed with saturated aqueous NaCl, dried over MgSO₄, filtered andevaporated to give a residue (218 g) as a colorless oil.

b) A solution of aniline (83.7 g, 0.9 mole), bromocarbamate from part a(146.0 g, 0.92 mole) and diisopropylethylamine (90.3 g, 0.7 mole) inbenzene (700 mL) was heated at reflux for 24 hours. The reaction mixturewas allowed to cool to room temperature and water (500 mL) was thenadded, and the organic layer was separated, washed with saturatedaqueous NaCl, dried over MgSO₄, filtered and evaporated to give aresidue (118 g).

c) To the residue from part b (118 g, 0.57 mole) was added an ice coldsolution of concentrated HCl (120 mL) dissolved in water (200 mL). Withmechanical stirring and cooling at 0° C., a solution of sodium nitrite(41.4 g, 0.6 mole) in water (100 mL) was added dropwise. The mixture wasstirred for two hours at 0° C. and a solid precipitate formed. The solidwas collected by filtration, washed with water (2×100 mL), and dried invacuo to provide a greenish yellow solid (115 g).

d) To a suspension of zinc dust (115 g, 0.48 mole) in water (350 mL)with mechanical stirring was added dropwise a solution of the product ofpart c (115 g) in acetic acid (230 mL). The temperature of the mixturewas controlled between 5°-15° C. during the addition after which thecooling bath was removed and the mixture was stirred at 30° for 45minutes. Dichloromethane (700 mL) was added and the mixture wasfiltered. The organic layer was separated and washed with 10% aqueoussodium carbonate (2×350 mL), saturated aqueous NaCl, dried over MgSO₄,filtered and evaporated to give a residue (93 g). e) The residue of partd (93 g, 0.42 mole) was dissolved in dichloromethane (350 mL) and cooledto -40° C. while stirring, a solution of ethylmagnesium bromide (225 mL,2.0 M in tetrahydrofuran) was added dropwise maintaining the temperaturebelow -30° C. After the addition, the mixture was allowed to warm toroom temperature and then was heated at 40° C. for two days. Ice chips(500 g) were added with stirring, and the mixture was acidified with 3NHCl to pH 3. The phases were separated, and the aqueous phase wasextracted with 5% methanol in dichloromethane (2×300 mL). The combinedorganic solutions were washed with saturated aqueous NaCl, dried overMgSO₄, filtered and evaporated to give a solid residue. The solid wassuspended in 2% MeOH in dichloromethane (100 mL) and filtered to providethe desired product (28.7 g).

m.p. =219° C.

NMR (300 MHz, DMSO-d₆) 3.07-3.01 (2 H, m), 3.63 (2 H, t, J=5.5 Hz), 6.64(1 H, br s), 6.87 (1 H, t, J=7.5 Hz), 7.03 (2 H, d, J=8 Hz), 7.27 (2 H,t, J=8 Hz), 8.42 (1 H, br s).

Mass spectrum: M⁺ =177

Analysis Calc'd for C₉ H₁₁ N₃ O : C, 61.00; H, 6.26; N, 23.71.

Found: C, 60.83, H, 6.29; N, 23.72.

EXAMPLE 69 1-(2'- methylphenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V, R₁ =2-methylphenyl, R₂ =R₄ =H

The title compound was prepared according to Scheme V in an analogousmanner as Example 68 except ortho-toluidine was used in part b insteadof aniline. m.p.=>230° C.

NMR (300 MHz, DMSO-d₆), 2.23 (3 H, s), 2.99-2.93 (2 H, m), 3.22 (2 H, t,J=5 Hz), 6.78 (1 H, br s), 6.99 (1 H, dt, J=6 Hz, 1 Hz), 7.04 (1 H, d,J=7 Hz), 7.16 (2 H, d, J=7 Hz),8.19 (1 H, br s).

Mass spectrum: M⁺ =191

Analysis Calc'd for C₁₀ H₁₃ N₃ O : C, 62.8; H, 6.85; N, 21.97.

Found: C, 63.09; H, 6.95; N, 22.0

EXAMPLE 70 1-(3'-methylphenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V, R₁ =3-methylphenyl, R₂ =R₄ =H

The title compound was prepared according to Scheme V in an analogousmanner as Example 68 except meta-toluidine was used in part b instead ofaniline.

H NMR (300 MHz, DMSO-d₆). 2.26 (3 H, s), 3.05-2.98 (2 H, m), 3.61 (2 H,t, J=5 Hz), 6.63 (1 H, br s), 6.68 (1 H, d, J=7.0 Hz), 6.87-6.80 (2 H,m), 7.14 (1 H, t, J=7.5 Hz), 8.38 (1 H, br s).

m.p.=235°-236° C.

Mass spectrum: M⁺ =191

Analysis Calc'd for C₁₀ H₁₃ N₃ O : C, 62.8; H, 6.85; N, 21.97.

Found: C, 62.01; H, 6.91; N, 22.01

EXAMPLE 71 1-(4'-methylphenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V, R₁ =4-methylphenyl, R₂ =R₄ =H

The title compound was prepared according to Scheme V in an analogousmanner as example 68 except para-toluidine was used in part b instead ofaniline.

H NMR=(300 MHz, CDCl₃, CD₃ OD), 2.22 (3 H, s), 3.14 (2 H, t, J=5 Hz),3.52 (2 H, t, J=5 Hz), 6.87 (2 H, d, J=9 Hz), 7.03 (2 H, d, J=9 Hz) ,the two exchangeable NH protons are not observed under these conditions)

m.p.=218°-220° C.

Mass spectrum: M⁺ =191

Analysis Calc'd for C₁₀ H₁₃ N₃ O : C, 62.8; H, 6.85, N, 21.97.

Found: C, 59.5; H, 6.75; N, 21.09

EXAMPLE 72 1-(3'-cyanophenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V, R₁ =3-cyanophenyl, R₂ =R₄ =H

The title compound was prepared according to Scheme V in an analogousmanner as Example 68 except 3-amino-benzonitrile was used in part binstead of aniline.

H NMR (300 MHz CDCl₃), 3.36-3.30 (2 H, m), 3.75 (2 H, t, J=6 Hz), 5.14(1 H, br s), 6.51 (1 H, br s), 7.37-7.27 (3 H, m), 7.40 (1 H, q, J=7.5Hz)

m.p.=>220° C.

Mass spectrum: M⁺ =202

EXAMPLE 73 1-(3'-bromophenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V, R₁ =3-bromophenyl, R₂ =R₄ =H

The title compound was prepared according to Scheme V in an analogousmanner as Example 68, except 3-bromo-aniline was used in part b insteadof aniline.

H NMR (300 MHz, DMSO-d₆) 3.03-3.09 (2 H, m), 3.67 (2 H, t, J=6 Hz), 6.77(1 H, br s), 7.01-7.07 (2 H, m), 7.22 (2 H, t, J=7.5 Hz), 8.54 (1 H, brs)

m.p.=260°-262° C.

Mass spectrum: M⁺ =256

Analysis Calc'd for C₉ H₁₀ Br N₃ O: C, 42.21; H,3.94; N, 16.41; Br 31.2.

Found: C, 41.48; H, 3.89; N, 16.11; Br, 31.18.

EXAMPLE 74 1-(3'-ethylphenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V, R₁ =3-ethylphenyl, R₂ =R₄ =H

The title compound was prepared according to Scheme V in an analogousmanner as Example 68, except 3-ethylaniline was used in part b insteadof aniline.

¹ H NMR (300 MHz, DMSO-d₆), 1.16 (3 H, t, J=7.5 Hz), 2.56 (2 H, q, J=7Hz), 3.01-3.07 (2 H, m), 3.62 (2 H, t, J=5 Hz), 6.63 (1 H, br s), 6.73(1 H, d, J=7.5 Hz), 6.82-6.9 (2 H, m), 7.16 (1 H, t, J=7.5 Hz), 8.38 (1H, br s)

m.p.=204°-205° C.

Mass spectrum: M⁺ =206

Analysis Calc'd for C₁₁ H₁₅ N₃ O: C, 64.37; H, 7.37; N, 20.47.

Found: C, 63.54; H, 7.28; N, 20.33

EXAMPLE 75 1-(3'-methylthiophenyl)-2H,4H-tetrahydro-1,2,4-

triazin-3-one

Formula V, R₁ =3-methylthiophenyl, R₂ =R₄ =H

The title compound was prepared according to

Scheme V in an analogous manner as Example 68, except3-methylthioaniline was used instead of aniline.

¹ H NMR (300 MHz, DMSO-d₆), 2.45 (3 H, s), 3.01-3.07 (2 H, m), 3.63 (2H, t, J=6 Hz), 6.67 (1 H, br s), 6.76 (1 H, d, J=7 Hz), 6.82 (1 H, dd,J=9 Hz, 1.5 Hz), 6.9 (1 H, t, J=1.5 Hz), 7.21 (1 H, t, J=8 Hz), 8.56 (1H, br s)

m.p.=179°-180° C.

Mass spectrum: M⁺ =224

Analysis Calc'd for C₁₀ H₁₃ N₃ O S: C, 53.79; H, 5.87; N, 18.82.

Found: C, 52.69; H, 5.82; N, 18.52

EXAMPLE 761-(3'-trifluoromethylphenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V, R₁ =3-trifluoromethylphenyl R₂ =R₄ =H

The title compound was prepared according to Scheme V in an analogousmanner as Example 68, except 3-trifluoromethylaniline was used in part binstead of aniline.

¹ H NMR (300) MHz, DMSO-d₆, 3.04-3.11 (2 H, m), 3.76 (2 H, t, J=5.5 Hz),6.79 (1 H, br s), 7.20 (1 H, d, J=7 Hz), 7.36 (2 H, d, J=10 Hz), 7.5 (1H, t, J=7.5 Hz), 8.63 (1 H,d, J=1.5 Hz)

m.p.=239°-241° C.

Mass spectrum: M⁺ =246

Analysis Calc'd for C₁₀ H₁₀ F₃ N₃ O: C, 48.98; H, 4.11; N, 17.14.

Found: C, 48.84; H, 4.20; N, 17.04

EXAMPLE 77 1-(3'-methoxyaniline)-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V, R₁ =3-methoxyaniline, R₂ =R₄ =H

The title compound was prepared according to Scheme V in an analogousmanner as Example 68, except 3-methoxyaniline was used in part b insteadof aniline.

¹ H NMR (300 MHz, DMSO-d₆), 3.01-3.09 (2 H, m), 3.62 (2 H, t, J=6 Hz),3.73 (3 H, s), 6.47 (1 H, dd, J=9, 2 Hz), 6.58 (1 H, t, J=2.5 Hz), 6.63(1 H, dd, J=9, 1 Hz), 6.75 (1 H , br s), 7.16 (1 H, t, J=8 Hz), 8.46 (1H, br s)

m.p.=183° C.

Mass spectrum: M⁺ =208

Analysis Calc'd for C₁₀ H₁₃ N₃ O₂ : C, 57.96; H, 6.32; N, 20.28.

Found: C-57.56; H, 6.15; N, 20.18

EXAMPLE 78 1-(3'-chlorophenyl)-2H,4H, tetrahydro-1,2,4-triazin-3-oneFormula V, R₁ =3-chlorophenyl, R₂ =R₄ =H

The title compound was prepared according to Scheme V in an analogousmanner as Example 68, except 3-chloroaniline was used in part b insteadof aniline.

1H NMR (300 MHz, DMSO-d₆), 3.03-3.09 (2 H, m), 3.67 (2 H, t, J=5 Hz),6.72 (1H, br s), 6.9 (1 H, dd, J=9, 1.5 Hz), 7.01 (1 H, dd, J=9, 1.5Hz), 7.07 (1 H, t , J=2.5 Hz), 7.27 (1 H, t, J=8 Hz), 8.53 (1 H, br s)

m.p.=244°-245° C.

Mass spectrum: M⁺ =212

Analysis Calc'd for C₉ H₁₀ Cl N₃ O: C, 51.07; H, 4.76; N, 19.85.

Found: C-50.28; H, 4.79; N, 19.47

EXAMPLE 79 1-(3'-benzyloxyphenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V, R₁ =3-benzyloxyphenyl, R₂ =R₄ =H

The title compound was prepared according to Scheme V in an analogousmanner as Example 68, except 3-benzyloxyaniline was used in part binstead of aniline.

1H NMR (300 MHz, DMSO-d₆), 3.01-3.07 (2 H, m), 3.62 (2 H, t, J=6 Hz),5.06 (2H, s), 6.54 (1 H, dd, J=9, 1.5 Hz), 6.61-6.66 (2 H, m), 6.68 (1H, t, J=2 Hz), 7.17 (1 H t J=8 Hz), 7.28-7.47 (5 H, m), 8.42 (1 H, d,J=1 Hz)

m.p.=169° C.

Mass spectrum: M⁺ =284

EXAMPLE 80 1-(3',5'-dimethylphenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V, R₁ =3',5'- dimethylphenyl, R₂ =R₄ =H

The title compound was prepared according to Scheme V in an analogousmanner as Example 68, except 3,5-dimethylaniline was used in part binstead of aniline.

1H NMR (300 MHz, DMSO-d₆), 2.20 (6 H, s), 2.99-3.06 (2 H, m), 3.58 (2 H,t, J=5 Hz), 6.51 (1 H, s), 6.6 (1 H, brs), 6.65 (2 H, s), 8.33 (1 H, d,1.5 Hz)

m.p=255°-257° C.

Mass spectrum: M⁺ =206

Analysis Calc'd for C₁₁ H₁₅ N₃ O: C, 64.37; H, 7.37; N, 20.47.

Found: C-63.67; H, 7.47; N, 20.21

The following compounds shown in Table 5 may be prepared according tothe method of Scheme V in an analogous manner as Example 68 exceptsubstituting the appropriate substituted analine (1).

                  TABLE 5                                                         ______________________________________                                        Phenyl substituted triazinones of Formula V,                                   ##STR36##                                                                    Example                                                                       ______________________________________                                                   Z =                                                                a          meta-2-furanyl                                                     b          para-2-furanyl                                                     c          meta-3-furanyl                                                     d          meta-2-thiophenyl                                                  e          para-2-thiophenyl                                                  f          meta-3-thiophenyl                                                  g          meta-2-thiazolyl                                                   h          meta-2-oxazolyl                                                    i          meta-2-benzothiophenyl                                             j          meta-2-pyridinyl                                                   k          meta-3-pyridinyl                                                   k          meta-4-pyridinyl                                                   l          meta-5-pyrimidinyl                                                 k          meta-phenoxy                                                       l          meta-COCH.sub.3                                                    m          para-COCH.sub.2 CH.sub.2 CH.sub.3                                  n          meta-COCH.sub.2 CH.sub.2 CO.sub.2 H                                o          meta-CH.sub.2 CH.sub.2 CH.sub.2 CO.sub.2 H                         p          meta-CH.sub.2 CH.sub.2 CN                                          q          meta-CH.sub.2 CH.sub.2 CONH.sub.2                                  r          meta-CH.sub.2 OCH.sub.3                                            s          meta-CH.sub.2 CH.sub.2 OH                                          t          meta-CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.3                u          meta-CH(CH.sub.3)N(OH)COCH.sub.3                                   v          meta-CH(CH.sub.3)N(OH)CONH.sub.2                                   w          meta-CHCHCH(CH.sub.3)N(OH)COCH.sub.3                               x          meta-CHCHCH(CH.sub.3)N(OH)CONH.sub.2                               y          meta-CH(CH.sub.3)CO.sub.2 H                                        z          meta-CH(CH.sub.3)NHCONH.sub.2                                      aa         meta-C(CH.sub.3)NOCH.sub.3                                         bb         meta-C(CH.sub.3)NN(CH.sub.3).sub.2                                 cc         meta-C(CH.sub.3)NHCO.sub.2 CH.sub.3                                dd         meta-C(CH.sub.3)NHCSNH.sub.2                                       ee         meta-CH.sub.2 CH.sub.2 CH.sub.2 NHC(NH)NH.sub.2                    ff         meta-CH.sub.2 CH.sub.2 CH.sub.2 NHC(NCN)NH.sub.2                   ______________________________________                                        Formula V compounds                                                           example    R.sub.1      R.sub.2    R.sub.4                                    ______________________________________                                        gg         phenyl       5-methyl   H                                          hh         phenyl       5-butyl    H                                          ii         phenyl       5-benzyl   H                                          jj         phenyl       5-isobutyl H                                          kk         phenyl       phenyl     H                                          ll         phenyl       cyano      H                                          mm         phenyl       H          CH3                                        nn         phenyl       H          benzyl                                     oo         3-ethylphenyl                                                                              ethyl      H                                          ______________________________________                                    

b) Scheme VI

Triazinone compounds of this invention of Formula V can be preparedaccording to Scheme VI. Treatment of a substituted hydroxyamine 19 withethylchloroformate (or an alternate alkyl or arylchloroformate, ClCO₂ R)in the presence of an appropriate base such as potassium carbonateprovides the hydroxycarbamate intermediate 20. Then 20 is oxidized tothe corresponding aldehyde 21. The aldehyde intermediate 21 is subjectedto reductive amination with the amine 1 to provide the intermediate 22.Nitrosation to the nitroso compound 23 is followed by reduction to thehydrazine intermediate 24 which is then cyclized by treatment with abase such as ethylmagnesium bromide to provide the substitutedtriazinone compounds of Formula V. ##STR37##

EXAMPLE 81 D,L-5-methyl-1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V, R₁ =phenyl, R₂ =methyl; R₄ =H

a) A solution of D,L-2-amino-1-propanol (7.51 g, 0.10 mol) in dryacetonitrile (100 ml) containing solid anhydrous potassium carbonate(27.6 g, 0.20 mol) was vigorously stirred by a mechanical stirrer andchilled to -20° C. while a solution of methylchloroformate (9.45 g, 0.10mol) in dry acetonitrile (20 mL) was introduced over a period of 30 min.The reaction mixture was stirred overnight at room temperature, filteredand the filtrate concentrated in vacuo to give the crude urethane, whichwas used directly without further purification.

b) To a stirred solution of oxalyl chloride (4.36 g, 34.0 mmol) inmethylene chloride (30 mL) at -78° C. was added, dropwise, a solution ofdimethylsulfoxide (5.28 g, 68.0 mmol) in methylene chloride (10 mL) overa 15 min. period and the mixture was stirred for another 15 min. at -78°C. To this mixture was added a solution of the urethane prepared in parta (3.01 g,22.6 mmol) in methylene chloride (30 mL) and the mixture wasstirred for one hour at -78° C. Triethylamine (7.26 g, 72.0 mmol) wasintroduced and the reaction mixture was allowed to warm to roomtemperature, filtered and the filtrate concentrated in vacuo at 30° C.The residue was used directly in the next step.

c) The residue from part b was dissolved in methanol (100 mL), treatedwith aniline (2.05 g, 22.0 mmol) and the mixture adjusted to pH 5-6 with10% ethanolic HCl. Sodium cyanoborohydride (1.57 g, 25 mmol) was addedand the mixture stirred under a nitrogen atmosphere at room temperature.Enough additional 10% ethanolic HCl was added to keep the pH near 5-6.After stirring overnight at room temperature, the reaction mixture wasrendered acidic with 10% ethanolic HCl and concentrated in vacuo at 30°C. The residue was taken up in methylene chloride (100 mL) and washedtwice with 10-20 ml portions of aqueous potassium carbonate solution.The organic layer was dried over magnesium sulfate, concentrated and theresidue was purified by chromatography (silica gel, methylene chlorideether) to provide 2.09 g of the anilino urethane.

d) A solution of the anilino urethane from part c (4.54 g, 0.021 mol) ina mixture of concentrated hydrochloric acid (4.5 mL) and water (20 mL)was chilled to -10° C. while a solution of sodium nitrite (1.66 g, 0.02mol) in water (4 mL) was slowly added with mechanical stirring. Themixture became thick and difficult to stir so dimethoxyethane (15 mL)was added to facilitate the stirring. After another hour of stirring at0° C., the mixture was extracted with benzene, the extracts dried overmagnesium sulfate and concentrated to yield 5.05 g of the nitrosourethane.

e) A suspension of zinc dust (5.30 g, 0.08 mol) in water (15 mL) wasmagnetically stirred and cooled to 15° C. while a solution of thenitroso urethane from part d (5.05 g, 0.021 mol) in glacial acetic acid(12 mL) was introduced at a rate so as to maintain the internaltemperature in the 15°-20° C. range. External cooling was removed andthe reaction mixture was stirred at room temperature during which timethe internal temperature spontaneously rose to 55° C. After one hour ofadditional stirring, the reaction was diluted with water (100 mL) andmethylene chloride (100 mL) and treated with 15% sodium hydroxidesolution to pH 6. The layers were decanted from the zinc residue and theorganic layer separated and dried over magnesium sulfate. Removal of thesolvent provided the crude hydrazino compound (4.28 g).

f) A solution of the hydrazino compound from part e (4.28 g, 0.019 mol)in methylene chloride (25 mL) was chilled to -25° C. while a 2M solutionof ethylmagnesium bromide in tetrahydrofuran (12.5 ml,0.025 mol) wasadded dropwise with stirring and under an atmosphere of nitrogen. Thereaction mixture was gently warmed (45° C.)for two days, treated withice and water, adjusted to pH 3-4 with 6N hydrochloric acid and thelayers separated. A portion of the product was isolated at this point byfiltration while the remainder was isolated by evaporation of themethylene chloride layer. The combined solids were crystallized fromethanol to provide 1.15 g of the title compound.

m.p. 238°-240° C.

1H NMR (300 MHz, DMSO-d₆) 1.00 (3H, d, J=6.0 Hz), 2.89 (1H, dd, J=15,10.5 Hz), 3.25 (1H, m), 4.03 (1H, dd, J=13.5, 4.5 Hz), 6.68 (1H, s),6.86 (1H, t, J=7.5 Hz), 7.03 (2H, d, J=7.5 Hz), 7.25 (2H, t, J=7.5 Hz),8.42 (1H, d, J=1.5 Hz).

Mass spectrum (M+H)⁺ =192

Anal Calc'd for C₁₀ H₁₃ N₃ O: C, 62.81; H, 6.85; N, 21.97.

Anal.

Found: C, 63.27; H, 6.86; N, 22.11.

EXAMPLE 82 D,L-5-i-propyl-1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V, R₁ =phenyl, R₂ =i-propyl. R₄ =H

The title compound was prepared according to Scheme VI in an analogousmanner as Example 81 except using D,L-2-amino-3-methyl-1-butanol insteadof D,L-2-amino-1-propanol.

m.p.=181°-182° C.

1H NMR (300 MHz, DMSO-d₆) 0.85 (6H, d, J=7.5 Hz), 1.64 (1H, m),2.96-3.12 (2H, m), 4.00 (1H, d, J=7.5 Hz),6.56 (1H, br s), 6.86 (1H, t,J=7.5 Hz), 7.03 (2H, d, J=7.5 Hz), 7.26 (2H, t, J=7.5 Hz), 8.44 (1H, d,J=1.5 Hz).

Mass spectrum: (M+H)⁺ =220

Anal. Calc'd for C₁₂ H₁₇ N₃ O: C, 65.73; H, 7.81; N, 19.16. Anal. Found:C, 65.86; H, 7.77; N, 18.42.

EXAMPLE 83 D,L-5-n-butyl-1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V, R₁ =phenyl, R₂ =n-butyl, R₄ =H

The title compound was prepared according to Scheme VI in an analogousmanner as Example 81 except using D,L-2-amino-1-hexanol instead ofD,L-2-amino-1-propanol.

m.p.=153°-155° C.

1H NMR (300 MHz, DMSO-d₆) 0.83 (3H, t, J=7.5 Hz), 1.10-1.50 (6H, m),2.99 (1H, dd, J=15, 10.5 Hz), 3.09-3.19 (1H, m), 4.03 (1H, dd, J=13.5,4.5 Hz), 6.62 (1H, s),6.86 (1H, t, J=7.5 Hz), 7.04 (2H, d, J=7.5 Hz),7.26 (2H, t, J=7.5 Hz), 8.42 (1H, d, J=1.5 Hz).

Mass spectrum: (M+H)+=234

Anal calc'd for C₁₃ H₁₉ N₃ O: C, 66.92; H, 8.21; N, 18.01.

Anal Found: C, 66.17; H, 8.05; N, 17.47.

EXAMPLE 84D,L-5-methyl-1-(3-methylphenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V, R₁ =3-methylphenyl, R₂ =methyl R₄ =H

The title compound was prepared according to Scheme VI in an analogousmanner as example 81 using 3-toluidine in part c instead of aniline.

m.p.=228°-229° C.

1H NMR (300 MHz, DMSO-d₆) 1.0 (3H, d, J=6 Hz), 2.26 (3H, s), 2.86 (1H,dd, J=13, 10 Hz), 3.21-3.31 (1H,m), 4.03 (1H, dd, J=13, 4.5 Hz),6.57-6.62 (2H, m), 6.8-6.87 (2H, m), 7.13 (1H, t, J=7.5 Hz), 8.39 (1H,br s).

Mass spectrum: (M)⁺ =206

Anal calc'd for C₁₁ H₁₅ N₃ O: C, 64.37; H, 7.37; N, 20.47.

Anal Found: C, 64.05; H, 7.43; N, 20.38.

EXAMPLE 85D,L-5-methyl-1-(3-chlorophenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V, R₁ =3-chlorophenyl, R₂ =methyl, R₄ =H

The title compound was prepared according to Scheme VI in an analogousmanner as example 81 using 3-chloroaniline in part c instead of aniline.

m.p.=246°-247° C.

1H NMR (300 MHz, DMSO-d₆) 1.02 (3H, d, J=7 Hz), 2.92 (1H, dd, J=13, 10Hz), 3.22-3.33 (2H, m), 4.08 (1H, dd, J=13, 4 Hz), 6.77 (1H, br s), 6.88(1H, d, J=7.5 Hz), 7.01 (1H, dd, J=7.5, 1.0 Hz), 7.27 (1H, t, J=7.5 Hz),8.53 (1H, d, J=1 Hz).

Mass spectrum: (M)⁺ =226

Anal calc'd for C₁₁ H₁₂ ClN₃ O: C, 53.22; H, 5.36; N, 18 62.

EXAMPLE 86 D,L-5-ethyl-1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V, R₁ =phenyl, R₂ =ethyl, R₄ =H

The title compound was prepared according to Scheme VI in an analogousmanner as example 81 using D,L-2-amino-1-butanol in part a instead ofD,L-2-amino-1-propanol.

m.p.=205° C.

1H NMR (300 MHz, DMSO-d₆) 0.82 (3H, t, J=7 Hz), 1.3-1.45 (2H, m), 2.99(1H, dd, J=12, 10 Hz), 3.03-3.12 (2H, m), 4.04 (1H, dd, J=13, 3 Hz),6.68 (1H, br s), 6.85 (1H, t, J=7.5 Hz), 7.03 (2H, d, J=7.5 Hz),7.25(2H, t, J=7.5 Hz), 8.39 (1H, br s).

Mass spectrum: (M)⁺ =206

Anal calc'd for C₁₁ H₁₅ N₃ O: C, 64.37; H, 7.37; N, 20.47.

Anal Found: C, 64.05; H, 7.39; N, 20.46.

EXAMPLE 87 5,5-dimethyl-1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V, R₁ =phenyl, R₂ =5,5-dimethyl, R₄ =H

The title compound was prepared according to Scheme VI in an analogousmanner as example 81 using 2-amino-2-methyl-1-propanol in part a insteadof D,L-2-amino-1-propanol.

m.p.=273° C.

1H NMR (300 MHz, DMSO-d₆) 0.95 (6H, s), 3.58 (2H, s), 6.72 (1H, t, J=7.5Hz), 6.81(1H, br s), 7.01 (2H, d, J=7.5 Hz), 7.2 (2H, t, J=7.5 Hz), 8.39(1H, br s).

Mass spectrum: (M)⁺ =206

Anal calc'd for C₁₁ H₁₅ N₃ O: C, 64.37; H, 7.37; N, 20.47.

Anal Found: C, 64.39; H, 7.34; N, 20.55.

c) Scheme VII

Triazinone compounds of Formula VI can be prepared by the methodillustrated in scheme VII, which involves the reaction of a haloethylisocyanate (25) with a substituted hydrazine (26) in an appropriatesolvent to provide the semicarbazide intermediate (27). Substitutedisocyanates (25), are prepared and manipulated by methods known to oneskilled in the art. The intermediate (27) is subjected to conditions toeffect intramolecular cyclization to the triazinone structure as inFormula VI.

As the intermediate (27) forms, it separates from the solution as asolid, and if desired, can be isolated by filtration, for example. Thereaction will proceed at room temperature and it may be heated to thereflux temperature depending on the solvent employed. The hydrazineintermediate (27) is then cyclized in the presence of a polar aproticsolvent such as, dimethylformamide (DMF), dimethylsulfoxide, orhexamethylphosphoric triamide to form the triazinone VI. A preferredsolvent is DMF. Cyclization is preferably conducted at elevatedtemperatures, from about 70° C. to about 100° C. Most preferred is thetemperature range from about 70° C. to about 75° C. A preferredcyclization reaction which allows for increased yields at lowertemperatures takes place in the presence of sodium iodide. The foregoingmay be better understood from the following examples, which arepresented for the purposes of illustration and are not intended to limitthe scope of the inventive concepts disclosed herein. ##STR38##

EXAMPLE 88 1-(3-fluorophenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula VI, R₁ =3-flurophenyl, R₂ =H

a). To a stirred suspension of 3-fluorophenylhydrazine hydrochloridesalt (4.06 g, 25 mmol) in dichloromethane (150 mL) was addedtriethylamine (2.5 g, 25 mmol). The mixture was stirred for 15 min.after which 2-chloroethylisocyanate (2.6 g, 25 mmol) was added dropwise.The mixture was stirred for 2 hours after which water was added (100mL). The organic layer was separated, washed with aqueous saturatedNaCl, dried over MgSO₄, filtered, and evaporated to give a solid (5.03g).

b). The residue from part a (2.3 g, 10 mmol) was dissolved in drydimethylformamide (20 mL) and NaI (2.99 g, 20 mmol) was added. Themixture was stirred at 75° C. for 48 h after which the mixture wasallowed to cool to room temperature. Water (10 mL) was added and theiodine color was removed by adding a saturated solution of NaHSO₃. ThepH of the mixture was adjusted to 8-9 by adding 2N NaOH. The mixture wasevaporated to give an oil which was purified by chromatography (silicagel, 7% methanol in dichloromethane) to provide the title compound (0.8g).

m.p.=194°-196° C.

1H NMR (300 MHz, DMSO-d₆) 2.17-2.23 (2H, m), 2.8 (2H, t, 6 Hz), 5.79(1H, dt, J=8, 1.5 Hz), 5.85 (1H, br s), 5.94-6.04 (2H, m), 6.36-6.44(1H, m), 7.76 (1H, br s).

Mass spectrum: (M+H)⁺ =196

Anal calc'd for C₉ H₁₀ FN₃ O: C, 55.38; H, 5.16; N, 21.53.

Anal Found: C, 55.67; H, 5.12; N, 21.61.

EXAMPLE 89 1-(3-nitrophenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula VI, R₁ =3-nitrophenyl, R₂ =H

The title compound was prepared according to Scheme VII in an analogousmanner as Example 88 using 3-nitrophenyl-hydrazine in part a instead ofphenylhydrazine.

m.p.=205°-208° C.

1H NMR (300 MHz, DMSO-d₆) 3.06-3.14 (2H, m), 3.79 (2H, t, J=5 Hz), 6.82(1H, br s), 7.49-7.59 (2H, m),7.68-7.74 (1H, m), 7.83 (1H, t, J=2 Hz),8.73 (1H, br s).

Mass spectrum: (M+NH₄)⁺ =240

Anal calc'd for C₉ H₁₀ N₄ O₃ : C, 48.65; H, 4.54; N, 25.22.

Anal Found: C, 49.23; H, 4.76; N, 24.61.

EXAMPLE 90 1-(2-pyridyl)-2H,4H-tetrahydro-1,2,4-triazin-3-one FormulaVI, R₁ =2-pyridyl, R₂ =H

The title compound was prepared according to Scheme VII in an analogousmanner as Example 88 using 2-pyridylhydrazine in part a instead ofphenylhydrazine.

m.p.=174°-176° C.

1H NMR (300 MHz, DMSO-d₆) 3.06-3.13 (2H, m), 3.87 (2H, t, J=6 Hz), 6.77(1H, br s), 6.80-6.85 (1H, m), 7.03 (1H, d, J=7.5 Hz), 7.64-7.7 (1H, m),8.15-8.2 (1H, m), 8.63 (1H, br s).

Mass spectrum: (M+H)⁺ =179

Anal calc'd for C₈ H₁₀ N₄ O: C, 53.92; H, 5.66; N, 31.44.

Anal Found: C, 53.49; H, 5.72; N, 30.80.

EXAMPLE 91 1-(2-benzothiazolyl)-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula VI, R₁ =2-benzothiazolyl, R₂ =H

The title compound was prepared according to Scheme VII in an analogousmanner as Example 88 using 2-hydrazino-benzothiazole in part a insteadof phenylhydrazine.

m.p.=249°-252° C.

1H NMR (300 MHz, DMSO-d₆) 3.31-3.36 (2H, m), 3.53-3.6 (2H, t, J=7 Hz),7.09 (1H, dt, J=7.5 , 1 Hz),7.15 (1H, br s), 7.27 (1H, dt, J=7.5, 1 Hz),7.45 (1 H, d, J=7.5 Hz) 7.75 (1H, d, J=7.5 Hz), 9.75 (1H, br s).

Mass spectrum: (M+H)⁺ =235

Anal calc'd for C₁₀ H₁₀ N₄ OS: C, 51.27; H, 4.30; N, 23.92.

Anal Found: C, 51.19; H, 4.47; N, 23.53.

EXAMPLE 92 1-(3-quinolyl)-2H,4H-tetrahydro-1,2,4-triazin-3-one FormulaVI, R₁ =3-quinolyl, R₂ =H

The title compound was prepared according to Scheme VII in an analogousmanner as Example 88 using 3-hydrazino-quinoline in part a instead ofphenylhydrazine.

m.p.=184°-186° C.

1H NMR (300 MHz, DMSO-d₆) 3.1-3.17 (2H, m), 3.83 (2H, t, J=5 Hz), 6.82(1H, br s), 7.5-7.6 (2H, m), 7.73 (1H, d, J=3.0 Hz), 7.84-7.87 (1H, m),7.91-7.96 (1H, m), 8.67 (1H, d, J=1.5 Hz), 9.87 (1H, d, J=3 Hz).

Mass spectrum: (M+H)⁺ =229

Anal calc'd for C₁₂ H₁₂ N₄ O: C, 63.18; H, 5.30; N, 24.55.

Anal Found: C, 62.64; H, 5.44; N, 24.32.

EXAMPLE 93 1-(2-benzoxazolyl)-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula VI, R₁ =2-benzoxazolyl, R₂ =H

The title compound was prepared according to Scheme VII in an analogousmanner as Example 88 using 2-hydrazino-benzoxazole in part a instead ofphenylhydrazine.

m.p.=240°-241° C.

1H NMR (300 MHz, DMSO-d₆) 3.28-3.34 (2H, m), 3.83 (2H, t, J=5 Hz), 7.08(1H, br s), 7.16 (1H, dt, J=7.5, 1.5 Hz), 7.25 (1H, dt, J=7.5, 1.5 Hz),7.45 (1H, d, J=7.5 Hz), 7.55 (1H, d, J=7.5 Hz), 9.05 (1H, br s).

Mass spectrum: (M+H)⁺ =219

Anal calc'd for C₁₀ H₁₀ N₄ O: C, 55.04; H, 4.62; N, 25.68.

Anal Found: C, 54.23; H, 4.49; N, 25.17.

d) Scheme VIII

A process for the preparation of triazinone compounds with substitutionat the 5-position is outlined in Scheme VIII. Treatment of anappropriately substituted chloramine derivative (28, R₂ =CO₂ CH₃) withphosgene or similar equivalent provides an isocyanate intermediate 29which was not isolated but subsequently treated with an arylhydrazine,(of the formula R₁ N₂ H₃) which in this example phenylhydrazine is shownto illustrate the process, and provides the intermediate semicarbazide30. Intramolecular cyclization of 30 by heating in an appropriatesolvent such as dimethylformamide (DMF) in the presence of NaI providesthe triazinone 31. The carboxyester group at position 5 in thetriazinone 31 can be in turn converted into various other derivativessuch as a hydroxy group by reduction or an amide group by substitutionreactions with an amine. Thus, 31 can serve as a useful intermediate toother 5-substituted triazinone compounds by one skilled in the art.##STR39##

EXAMPLE 94 D,L-5-carbomethoxy-1-phenyl-2H-tetrahydro-1,2,4-triazin-3-oneFormula VI, R₁ =phenyl, R₂ =5-carbomethoxy

a). D,L-2-Amino-3-chloropropionic acid methyl ester hydrochloride (28).The title compound was prepared in 85% yield from DL-serine methyl esterhydrochloride according to the method of Plattner, et al., Helv ChimActa, 40, 1531 (1957).

m.p.126°-130° dec (lit. m.p. 134°-136°).

b). 4-[(1-carbomethoxy-2-chloro)ethyl]-1-phenylsemicarbazide (30). Asuspension of D,L-2-amino-3-chloropropionic acid methyl esterhydrochloride (26.8 g, 0.15 mol) in toluene (250 mL) was stirred atreflux temperature while a solution of phosgene in toluene (160 mL of a1.93 M solution, 0.309 mol) was introduced dropwise in 40 mL portions at30 minute intervals. The nearly clear, yellow-orange reaction mixturewas heated at reflux for 30 minutes longer and then kept at roomtemperature overnight. The mixture was filtered to remove solids and thefiltrate was concentrated in vacuo, to provide the crude isocyanatewhich was taken up in dry ether (250 mL) and added dropwise at roomtemperature under nitrogen to a stirred solution of phenylhydrazine(12.9 g, 0.12 mol) in dry ether (250 mL). The mixture was stirredovernight under a nitrogen atmosphere at room temperature, filtered andthe filtrate washed three times with 1N HCl to remove any remainingphenyl hydrazine. After drying over magnesium sulfate, the ether layerprovided, upon concentration, the title compound (31.7 g) which was ofsufficient purity to be used directly without further purification.

c). D,L-5-carbomethoxy-1-phenyl-2H-tetrahydro-1,2,4-triazin-3-one (31).A solution of the previously described semicarbazide (31.7 g) in drydimethylformamide (140 mL) was treated with sodium iodide (35.0 g, 0.23mol) and the mixture was stirred for two days at 75°-80° C. under anitrogen atmosphere. The mixture was allowed to cool, was treated withsaturated aqueous sodium bisulfite (10 mL) and diluted with water (150mL). Aqueous NaOH (6N) was added to adjust the solution to pH 7-8 andthe mixture was filtered to isolate a portion of the crystalline titlecompound which was washed several times with water. The aqueous DMFfiltrate was concentrated in vacuo at 50°-55° C. to remove most of thewater and the residue was distilled at 50°-60° C. and 0.1 mm-Hg toremove most of the DMF. The residue was partitioned between water (100mL) and ethyl acetate (200 mL). After drying over magnesium sulfate, theethyl acetate layer was concentrated and the residue was triturated indichloromethane (20 mL). The remaining portion of the title compound wascollected by filtration and washed free of all color with portions ofdichloromethane. The total yield was 4.65 g. Decomposition at 209°-212°C. with gas evolution.

1H NMR (300 MHz, DMSO-d₆) 3.40 (3 H, s), 3.77-3.90 (1H, m), 3.90-4.02 (2H, m), 6.81-6.94 (2 H, m), 7.02 (2H,d,J=7.5 Hz),7.25 (2H, t, J=7.5 Hz),8.66 (1 H, d, J=2.0 Hz).

Mass spectrum: (M+H)⁺ =236

Anal. Calc'd for C₁₁ H₁₃ N₃ O₃ : C, 56.16; H, 5.57; N, 17.86. Anal.found: C, 55.70; H, 5.58; N, 17.88.

The carboxy ester group at position - 5 on the triazinone ring can beconverted to various other derivatives such as a hydroxy group byreduction or an amide group by a substitution reaction with an amine.Thus compounds of Formula VI may be useful intermediates to prepareother 5-subsituted triazinone compounds.

The following example illustrates the utility of Example 94 as anintermediate.

EXAMPLE 95D,L-5-(1-hydroxy-1-methylethyl)-1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-one.Formula VI, R₁ =phenyl, R₂ =1-hydroxy-1-methylethyl

A suspension of the title compound of Example 94 (0.118 g, 0.5 mmol) indry tetrahydrofuran (10 mL) was cooled to -20° C. and treated with asolution of methylmagnesium bromide (1.1 mL of a 2.9 M solution inether, 3.2 mmol). The mixture was stirred for 1 h, allowed to warm toroom temperature, and saturated aqueous NH₄ Cl (2.0 mL) was added. Themixture was adjusted to pH=2 with 3N HCl and the organic layer wasseparated and concentrated. The residue was purified by chromatography(silica gel, methanol-dichloromethane 1:20) to give the title compound(103 mg).

m.p.=224°-226° dec.

1H NMR (300 MHz, DMSO-d₆) 1.06 (6H, s), 2.94-3.13 (2H, m), 4.09 (1H, dd,J=4.5,13.5 Hz), 4.62 (1H, s), 5.98 (1H, br s), 6.87 (1H, t, J=7.5 Hz),7.04 (2H, d, J=7.5 Hz), 7.28 (2H, t, J=7.5 Hz), 8.56 (1H, d, J=1.5 Hz).

Mass spectrum: (M+H)⁺ =236

Anal. Calc'd for C₁₂ H₁₇ N₃ O₂ : C, 61.26; H, 7.28; N, 17.86. Anal.found: C, 60.85; H, 7.27; N, 17.64.

The following compounds shown in Table 6 are prepared according to themethod of Scheme VIII in an analogous manner as Example 94 exceptsubstituting the appropriate chloroamine derivative for 28 and theappropriate aryl or heteroaryl hydrazine for phenylhydrazine.

                  TABLE 6                                                         ______________________________________                                        Formula VI compounds                                                          Example                                                                              R.sub.1 =       and R.sub.2 =                                          ______________________________________                                        a      meta-chlorophenyl                                                                             --CONH.sub.2                                           b      meta-methylphenyl                                                                             --CN                                                   c      meta-chlorophenyl                                                                             --CH.sub.2 OCH.sub.2 CO.sub.2 H                        d      meta-chlorophenyl                                                                             --CH.sub.2 OCH.sub.2 CH.sub.2 OH                       e      meta-phenoxy    --CH.sub.2 OCH.sub.2 CH.sub.2 CH.sub.2 CO.sub.2 H      f      4-pyridyl       --CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.3                g      meta-chlorophenyl                                                                             --CON(OH)CH.sub.3                                      h      4-pyridyl       --CH.sub.2 NHCH.sub.2 CO.sub.2 H                       i      2-pyridyl       --CH.sub.2 NHCH.sub.2 CO.sub.2 CH.sub.3                j      3-pyridyl       --CH.sub.2 NHCH.sub.2 CO.sub.2 H                       k      5-pyrimidyl     --CH.sub.2 NHCO.sub.2 CH.sub.3                         l      4-pyridyl       --CH.sub.2 NHCONH.sub.2                                m      meta-chlorophenyl                                                                             --COCH.sub.3                                           n      meta-chlorophenyl                                                                             --C═NOCH.sub.3                                     o      meta-methylphenyl                                                                             --CH.sub.2 OCH.sub.2 CH═CH.sub.2                   p      meta-chlorophenyl                                                                             --CH.sub.2 OCH.sub.2 C.tbd.CH                          q      2-benzothiazole --COCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                r      2-quinolyl      --CO.sub.2 CH.sub.3                                    s      3-(2-furanyl)phenyl                                                                           --CO.sub.2 CH.sub.3                                    t      3-(2-thiophenyl)phenyl                                                                        --CO.sub.2 CH.sub.3                                    u      3-(4-pyridyl)phenyl                                                                           -- CO.sub.2 CH.sub.3                                   v      3-(5-pyrimidyl)phenyl                                                                         --CO.sub.2 CH.sub.3                                    w      3-(3-pyridazinyl)phenyl                                                                       --CO.sub.2 CH.sub.3                                    v      3-(2-benzothio- --CO.sub.2 CH.sub.3                                           phenyl)phenyl                                                          w      3-(2-quinolinyl)phenyl                                                                        --CO.sub.2 CH.sub.3                                    x      3-(2-thiazolyl)phenyl                                                                         --CO.sub.2 CH.sub.3                                    y      3-(5-tetrazole)phenyl                                                                         --CO.sub.2 CH.sub.3                                    ______________________________________                                    

e) Scheme IX

Triazinone compounds of Formula VI substituted at the 5-position can bereadily prepared as outlined in Scheme IX. The reaction of a substitutedalkene (31) with iodine isocyanate provides an intermediate isocyanate(32) (the use of iodine isocyanate is a known method, Hassner, A.;Lorber, M. E.; Heathcock, C. J. Org. Chem. 1967, 32, 540.) which is notisolated but directly reacted with a substituted hydrazine (26) toprovide the semicarbazide intermediate (33) which is subsequentlycyclized to triazinone compounds of Formula VI as previouslydemonstrated. ##STR40##

EXAMPLE 965-(2-methoxyethoxymethyl)-1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-one.Formula VI, R₁ =phenyl, R₂ =2-methoxethoxy-methyl

a). Iodine (2.54 g, 10 mmol) was dissolved in anhydrous ether (20mL) andtreated with AgNCO (2 g, 13 mmol) at room temperature under nitrogen.The mixture was cooled to 0° C. and 3-(2-methoxyethoxy) propene (1.16 g,10 mmol) was added over 30 min. The mixture was stirred at roomtemperature for 2 h, filtered through Celite. The filtrate solution wasused directly in the next step.

b). The filtrate from part a was added dropwise to a stirred solution ofphenylhydrazine (1.08 g, 10 mmol) in ether (50 mL) at room temperature.The mixture was concentrated to give a crude residue which was purifiedby chromatography (silica gel, dichloromethane/methanol, 19:l) toprovide the iodosemicarbazide intermediate (1.6 g).

c). The iodosemicarbazide intermediate (1.05 g, 2.67 mmol) was dissolvedin ethanol (10 mL) and heated to reflux for 5 hours. The solvent wasevaporated and the residue was dissolved in dichloromethane (10 mL) andether was added to induce crystallization to give the desired product(228 mg).

m.p.=118°-120° C.

1H NMR (300 MHz, DMSO-d₆) 3.35 (3H, s), 3.44-3.96 (9H, m), 5.42 (1H, m),6.85 (2H, d, J=7.5 Hz), 6.92 (1H, t, J=7.5 Hz), 7.28 (2H, t, J=7.5 Hz),8.50 (1H, s).

Mass spectrum: (M+H)⁺ =266

The following compounds shown in Table 7 may be prepared according tothe method of Scheme IX in an analogous manner as Example 96 exceptsubstituting the appropriate olefin (31) and the appropriatelysubstituted aryl or heteroaryl hydrazine (26).

                  TABLE 7                                                         ______________________________________                                        Formula VI compounds                                                          Exam-                                                                         ple   R.sub.1 =   R.sub.2 =                                                   ______________________________________                                        a     meta-chloro-                                                                              --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CO.sub.2 CH.sub.3                       2                                                                 phenyl                                                                  b     meta-methyl-                                                                              --CH.sub.2 CH.sub.2 CO.sub.2 H                                    phenyl                                                                  c     2-pyridyl   --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CO.sub.2 H            d     4-pyridyl   --CH.sub.2 CH.sub.2 CH.sub.2 OH                             e     3-(2-       --CH.sub.2 CH.sub.2 CH.sub.2 CO.sub.2 CH.sub.3                    pyridyl)phenyl                                                          f     meta-chloro-                                                                              --CH.sub.2 CH.sub.2 CH.sub.2 CH(NH.sub.2)CO.sub.2 H               phenyl                                                                  g     2-benzothiazole                                                                           --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CO.sub.2                       CH.sub.3                                                    h     2-benzoxazole                                                                             --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 OH                    i     3-pyridyl   --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 NHCOCH.sub.3          j     meta-chloro-                                                            para --CH.sub.2 OC.sub.6 H.sub.4 CO.sub.2 H                                         phenyl                                                                  k     meta-chloro-                                                                              --CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.3                           phenyl                                                                  l     2-pyridyl   --CH.sub.2 OCH(CH.sub.3)CON(OH)CH.sub.3                     m     3-(2-       --CH.sub.2 OCH.sub.2 CO.sub.2 H                                   furanyl)phenyl                                                          n     3-(2-       --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 NHCOCH.sub.3                pyridyl)phenyl                                                          o     4-pyridyl   --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 NHCO.sub.2                              CH.sub.3                                                    p     meta-methyl-                                                                              --CH.sub.2 CH.sub.2 NHCONH.sub.2                                  phenyl                                                                  r     meta-methyl-                                                                              --CH.sub.2 CH.sub.2 NHC(═NH)NH.sub.2                          phenyl                                                                  s     2-pyridyl   --CH.sub.2 CH.sub.2 CH.sub.2 C(═NOH)CH.sub.3            t     2-pyridyl   CH.sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3)N(OH)COCH.sub. 3      u     2-pyridyl   --CH.sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3                                       )N(OH)CONH.sub.2                                            v     3-chloro-   --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 SO.sub.2 CH.sub.3           phenyl                                                                  w     3-methyl-   --CH.sub.2 CH.sub.2 SO.sub.2 CH.sub.3                             phenyl                                                                  x     2-pyridyl   --CH.sub.2 CH.sub.2 SOC.sub.6 H.sub.5                       ______________________________________                                    

f) Scheme X

Triazinone compounds with a substituent group at the 5-position can alsobe prepared from amino acid derivatives as outlined in Scheme X. Thecorresponding ester of an amino acid 34 is treated with an aryl orheteroaryl amine 1 in the presence of ethylmagnesium bromide to providethe corresponding aryl or heteroaryl amide 35 which is then reduced tothe amino compound 36 with a suitable reducing reagent such as lithiumaluminum hydride. Treatment of the intermediate 36 with a chloroformatesuch as methyl chloroformate in the presence of triethylamine providesthe carbamate 37. Nitrosation of 37 leads to the N-nitroso intermediate38 which is then reduced to the corresponding hydrazine intermediate 39with a reducing reagent such as zinc in acetic acid. Cyclization to thetriazinone of Formula VI is accomplished as previously described. Thismethod is illustrated by Example 97 utilizing the methyl esterhydrochloride salt of DL-serine. This method provides access to eitherof the two enantiomers of 5-substituted triazinones using D- or L-aminoacid starting materials. ##STR41##

EXAMPLE 97D,L-5-hydroxymethyl-1-phenyl-2H,4H,tetrahydro-1,2,4-triazin-3-oneFormula VI, R₁ =phenyl, R₂ =hydroxymethyl

a). A solution of aniline (2.79 g, 0.03 mol) in dichloromethane (10 mL)was cooled to 0° C. and stirred under nitrogen and a 2N solution ofethylmagnesium bromide in tetrahydrofuran (15.0 ml, 0.03 mol) was addeddropwise. The mixture was stirred for 30 min. followed by portionwiseaddition of DL-serine methyl ester hydrochloride (1.56 g, 0.01 mol) overa 1 h period. The thick reaction mixture was diluted with additionaldichloromethane (10 mL) and heated at reflux for three days. After beingallowed to cool, the mixture was treated with a saturated aqueous NH₄ Cl(5 mL) and extracted twice with dichloromethane (100 mL). Thedichloromethane layer was dried over MgSO₄, concentrated and the residuetitrated in pentane-ether (1:1) to give a solid product, m. p. 116°-118°C.

b). The product from part a (1.96 g, 0.01 mol) was dissolved in drytetrahydrofuran (50 mL) and added dropwise to a suspension of lithiumaluminum hydride (0.836 g, 0.022 mol) in dry tetrahydrofuran (35 mL)with stirring at room temperature under a nitrogen atmosphere. Themixture was stirred at reflux overnight, cooled and quenched by dropwiseaddition of water (0.9 mL), then followed by 15% NaOH solution (0.9 mL)and water (2.7 mL). The mixture was stirred for 3 h, filtered and thefiltrate was concentrated. The residue, which began to solidify within ashort time, was triturated in ether (10 mL) and the solid collected togive a solid product (1.2 g), m. p. 89°-92° C.

c). A mixture of the product from part b (1.20 g, 0.007 mol) andtriethylamine (0.73 g, 0.007 mol) in dry tetrahydrofuran (50 mL) wasstirred at -5° C. while a solution of methyl chloroformate (0.68 g,0.007 mol) in dry tetrahydrofuran (15 mL) was slowly introduced. Themixture was stirred at -5° C. for two hours, allowed to warm to roomtemperature and filtered. The filtrate was concentrated to give acarbamate intermediate (1.73 g).

d). A mixture of the product from part c (1.73 g, 0.0077 mol),concentrated hydrochloric acid (2.0 mL), water (10 mL) anddimethoxyethane (6 mL) was stirred at 0° C. and a solution of sodiumnitrite (0.59 g, 0.0085 mol) in water (1.0 mL) was added dropwise. Themixture was stirred at 0° C. for 1 hour, extracted with dichloromethane(100 mL) and the extract concentrated to give a residue (1.78 g).

e). To a stirred suspension of zinc dust (1.80 g, 0.027 mol) in water(5.3 mL) cooled to 15° C., was gradually added a solution of the residuefrom part d (1.78 g, 0.007 mol) in glacial acetic acid (4.5 mL). Afterthe addition, the cooling bath was removed and the mixture was stirredat room temperature for 1 h. Dichloromethane (10 mL) was added and themixture was adjusted to pH 6 with 15% NaOH. The organic and aqueouslayers were decanted from the zinc residue which was extracted with afresh portion (10 mL) of dichloromethane. The combined organic layerswere dried over MgSO₄ and concentrated to yield the hydrazineintermediate (1.53 g).

f). The hydrazine from part e (1.53 g, 0.006 mol) was dissolved indichloromethane (10 mL), chilled to -30° C. and treated with a 2Msolution of ethylmagnesium bromide in tetrahydrofuran (12.0 mL, 0.024mol). The mixture was heated at 45°-50° C. for four days, cooled andtreated with a solution of concentrated hydrochloric acid (2.0 mL) inmethanol (25 mL). The mixture was concentrated and the residue extractedwith 10% methanol in dichloromethane (4×25 mL). The extracts were driedover MgSO₄, concentrated and the residue purified by chromatography(silica gel, dichloromethane-methanol), to give the title compound.

m.p.=223°-224° C. dec.

1H NMR (300 MHz, DMSO-d₆) 3.08-3.30 (4H, m), 4.01 (1H, d, J=10.5 Hz),4.77 (1H, t, J=6.0 Hz), 6.46 (1H, br s), 6.86 (1H, t, J=7.5 Hz), 7.02(2H, d, J=7.5 Hz), 7.26 (2H, t, J=7.5 Hz), 8.47 (1H, d, J=1.5 Hz).

Mass spectrum: (M+H)⁺ =208

Anal calc'd for C₁₀ H₁₃ N₃ O₂ : C, 57.96; H, 6.32; N, 20.28.

Anal. Found: C, 57.54; H, 6.28; N 19.87.

Another preferred embodiment of this reaction scheme is by starting withan intermediate such as (36), for instance when R₁ is phenyl and R₂ =H.Treatment of phenylethylenediamine with ethylchloroformate andtriethylamine produces the carbamate intermediate (37). The carbamate(37) is reacted with sodium nitrate in the presence of an acid toproduce the N-nitroso intermediate which is reduced with a zinc catalystto provide the hydrazine intermediate (39). The hydrazine intermediate(39) is cyclized with ethylmagnesium bromide to produce triazinonecompounds of Formula VI as illustrated in the following example.

EXAMPLE 98 1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-one Formula VI, R₁=phenyl, R₂ =H

a) Ethyl chloroformate (70.6 mL, 0.735 mole) was slowly added to acooled (0°-5° C.) solution of N-phenylethylenediamine (100 g, 0.735mole) and triethylamine (104 mL, 0.735 mole) in dichloromethane (500 mL)while stirring under nitrogen and maintaining the reaction temperaturebelow 5° C. The mixture was stirred one hour, after which saturatedaqueous NH₄ Cl was added (200 mL) and the pH was adjusted to 6.5 with 3NHCl. The layers were separated, and the aqueous layer was extracted withdichloromethane (2×200 mL). The combined organic extracts were washedwith saturated aqueous NaCl, dried over MgSO₄, filtered and evaporatedto provide a residue (150 g).

b) The residue from part a (150 g, 0.721 mole) was suspended in a cold(5° C.) mixture of water (100 mL) and conc. HCl (160 mL). Withmechanical stirring a cold (5° C.) solution of NaNO₂ (52 g, 0.72 mole)in water (160° mL) was added slowly. The mixture was stirred for 30 min.and dichloromethane (500 mL) was added. The layers were separated, theorganic layer was washed with saturated aqueous NaCl, dried over MgSO₄,filtered and evaporated to give a residue (150 g).

c) The residue from part b (150 g, 0.63 mole) was dissolved in aceticacid (220 mL) and with mechanical stirring was added dropwise to asuspension of zinc (164 g, 2.5 mole) in water (400 mL). The temperatureof the reaction was maintained between 10°-15° C., and after theaddition the mixture was allowed to warm to room temperature for 45minutes. Dichloromethane (500 mL) was added and the mixture wasfiltered. The solids (excess zinc) were washed with dichloromethane(2×50 mL), and the combined organic extract was washed with 10% aqueousNa₂ CO₃, saturated aqueous NaCL, dried over MgSO₄, filtered andevaporated to provide a residue (135 g).

d) The residue from part c (135 g, 0.60 mole) was dissolved indicholormethane (500 mL) and cooled to -20° C. under nitrogen.Ethylmagnesium bromide (310 mL, 2M in tetrahydrofuran) was added slowly.The mixture was refluxed for two days. The mixture was allowed to cooland ice chips (200 g) were added whereupon a precipitate formed in theaqueous layer. The mixture was acidified to pH 3 with 3N HCl. Moredicholormethane (400 mL) was added, and the mixture was shaken for 5minutes after which, a new precipitate formed in the dicholormethanelayer. The organic layer together with suspended precipitate wasseparated from the aqueous layer and then cooled at 5° C. for 1-2 hours.The mixture was filtered while cold using a sintered funnel to provide asolid (52.5 g). This material was dissolved in a mixture of 10% methanolin chloroform and then washed with in HCl (100 mL) and evaporated togive a solid. This material was washed with dichloromethane (50 mL) anddried in vacuo to provide the desired product (47 g, 44%), mp 211°-213°C.

¹ H NMR (300 MHz, DMSO d6) 3.02 (2H, m), 3.62 (2H, t), 6.65 (1H, br s),6.83-7.23 (5H, m), 8.42 (1H, s).

Mass spectrum: M+=178

Anal Calc'd. for C₉ H₁₁ N₃ O : C, 61.00; H, 6.26; N, 23.71.

Anal. Found : C, 60.83; H, 6.29; N, 23.72.

A more preferred route to the products of example 98 is provided by themethod of Scheme VII in an analogous manner as example 88.

g) Scheme XI

Triazinone compounds with a substituent group at the 4-position can beprepared as outlined in Scheme XI. Acylation of a diamine startingmaterial 40, where the choice of the carboxylic acid chloride willdetermine the nature of the substituent R₄, provides the intermediateaminoamide 42. Reduction of 42 with a reducing agent such as lithiumaluminum hydride provides the substituted diamine 43 which is reactedwith a chloroformate such as methyl chloroformate in the presence of abase such as triethylamine to provide the intermediate carbamate 44. Thesequence of reactions involving nitrosation to the N-nitrosointermediate 45, reduction to the hydrazine 46, and cyclization asprevously described, provides triazinone compounds of Formula V.##STR42##

EXAMPLE 99 4-Benzyl-1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V, R₁ =phenyl, R₄ =benzyl

a). A mixture of N-phenylethylenediamine (24.4 g, 0.179 mol) andtriethylamine (18.1 g, 0.179 mol) in dichloromethane (100 mL) wasstirred and cooled in a ice-salt mixture while a solution of benzoylchloride (25.2 g, 0.179 mol) in dichloromethane (50 mL) was introduceddropwise at a rate so as to keep the internal temperature below 6° C.After being kept at room temperature overnight, the reaction mixture waswashed with 5% NH₄ Cl (2×75 mL), the organic layer was dried over MgSO₄and concentrated in vacuo to yield 37.8 g of product which could becrystallized from benzene. m. p. 125°-127° C.

b). To a suspension of LiAlH₄ (3.80 g, 0.10 mol) in dry tetrahydrofuran(100 mL) was added dropwise with stirring a solution of the compoundprepared in part a (12.02 g, 0.05 mol) in tetrahydrofuran (50 mL). Themixture was stirred at reflux overnight under a nitrogen atmosphere.After careful addition of water (3.8 mL), followed by 15% sodiumhydroxide solution (3.8 mL) and water (11.3 mL), the mixture was stirredat room temperature for 1.5 hr and filtered. Evaporation of the filtrateprovided the N-benzyl compound.

c). The intermediate from part b (11.29 g, 0.049 mol) was treated withmethyl chloroformate (4.68 g, 0.049 mol) and triethylamine (5.00 g,0.049 mol) in dichloromethane (100 mL) in a manner identical to part ato give the carbamate (13.8 g).

d). The carbamate from part c (13.8 g, 0.048 mol) dissolved indimethoxyethane (20 mL) was treated with concentrated hydrochloric acid(9.1 mL) in water (45 mL) and cooled to 5° C. while a solution of sodiumnitrite (3.33 g, 0.048 mol) in water (6 mL) was slowly introduced withstirring. The product which separated as a heavy oil was extracted intodichloromethane, dried over MgSO₄ and concentrated to give the nitrosointermediate.

e). A solution of the intermediate from part d (17.0 g, 0.054 mol) inglacial acetic acid (30 mL) was introduced dropwise into a mechanicallystirred suspension of zinc dust (14.2 g) in water (35 mL) which wascooled in ice water during the addition so that the internaltermperature remained in the 15°-20° C. range. The cooling bath wasremoved and the stirring continued for another hour during which timethe internal temperature reached 37° C. within 10 min. The reactionmixture was treated with dichloromethane (200 mL) and water (100 mL) andfiltered to remove zinc residue. The filtrate was treated with 6 Nsodium hydroxide solution to pH 6 and the layers were separated. Theorganic extract was dried over MgSO₄ and concentrated to give the crudehydrazine (16.0 g).

f). The hydrazine from part e (15.0 g, 0.05 mol) was dissolved indichloromethane (50 mL) and treated at -30° C. with 2M ethylmagnesiumbromide in tetrahydrofuran (31.0 mL, 0.062 mol) under nitrogen. Themixture was gently warmed at 45° C. for three days, cooled, treated withice and 3N hydrochloric acid to pH 4-5 and the layers separated. Theorganic layer was dried over MgSO₄, concentrated and the residuetriturated in ether. The crude product was crystallized from benzene togive 3.79 g of the title compound.

m.p.=164°-166° C.

¹ H NMR (300 MHz, DMSO-d₆) 3.02 (2H, t, J=6.0 Hz), 3.75 (2H t J=6.0 Hz)4.42 (2H s) 6.89 (1H, t, J=7.5 Hz), 7.02-7.15 (4H, m), 7.17-7.34 (5H,m), 8.71 (1H, s).

Mass spectrum: (M+H)⁺ =268

Anal Calc'd for C₁₆ H₁₇ N₃ O: C, 71.89; H, 6.41; N, 15.72.

Anal Found: C, 71.82; H, 6.50; N, 15.72.

EXAMPLE 100 4-Ethyl-1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V, R₁ =phenyl, R₄ =ethyl

The title compound was prepared according to Scheme XI in an analogousmanner as Example 99 except acetyl chloride was used in part a insteadof benzoyl chloride.

m.p.=152.5°-154.5° C.

¹ H NMR (300 MHz, DMSO-d₆) 0.94 (3H, t, J=7.5 Hz), 3.11 (2H, t, J=6.0Hz), 3.18 (2H, q, J=7.5 Hz), 3.73 (2H, t, J=6.0 Hz), 6.87 (1H, t, J=7.5Hz), 7.03 (2H, d, J=7.5 Hz), 7.26 (2H, t, J=7.5 Hz), 8.43 (1H, s)

Mass spectrum: (M+H)⁺ =206

Anal. Calc'd for C₁₁ H₁₅ N₃ O: C, 64.37; H, 7.37; N, 20.47.

Anal. Found: C, 64.22; H, 7.39; N, 20.36.

EXAMPLE 101 4-Methyl-1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V, R₁ =phenyl, R₄ =methyl

The title compound was prepared according to Scheme XI in an analogousmanner as Example 99 except methyl chloroformate was used in part ainstead of benzoyl chloride.

m.p.=174°-178° C.

¹ H NMR (300 MHz, DMSO-d₆) 2.73 (3H, s), 3.11 (2H, t, J=6.0 Hz), 3.74(2H, t, J=6.0 Hz), 6.87 (1H,t,J=7.5 Hz), 7.02 (2H, d, J=7.5 Hz), 7.26(2H,t, J=7.5 Hz), 8.49 (1H, s)

Mass spectrum: (M+H)⁺ =192

Anal. Calc'd. for C₁₀ H₁₃ N₃ O: C, 62.81; H, 6.85; N, 21.97.

Anal. Found: C, 62.54; H, 6.87; N, 21.82.

The following compounds of general Formula V shown In Table 8 areprepared according to the method of Scheme XI in an analogous manner asExample 99 except substituting the appropriate diamine 40 and acylchloride 41.

                  TABLE 8                                                         ______________________________________                                        Formula V compounds                                                           Example                                                                              R.sub.1       R.sub.2 =  R.sub.4 =                                     ______________________________________                                        a      meta-chlorophenyl                                                                           --CH.sub.2 CH.sub.3                                                                      CH.sub.2 C.sub.6 H.sub.5                      b      2-pyridyl     --CH.sub.3 CH.sub.2 OCH.sub.2 C.sub.6 H.sub.5            c      4-pyridyl     --CH.sub.2 (CH.sub.3).sub.2                                                              CH.sub.2 C.sub.6 H.sub.5                      d      4-pyridyl     --CH.sub.3 CH.sub.2 C.sub.6 H.sub.5                      e      2-pyridyl     --CH.sub.3 CH.sub.2 C.sub.6 H.sub.5                      f      2-benzothiophenyl                                                                           --CH.sub.3 CH.sub.2 C.sub.6 H.sub.5                      g      3-(2-pyridyl)phenyl                                                                         --CH.sub.3 CH.sub.2 C.sub.6 H.sub.5                      h      4-pyridyl     --CH.sub.3 (CH.sub.2).sub.3 CH.sub.3                     i      2-quinoyl     --CH.sub.3 CH.sub.2 C.sub.6 H.sub.5                      j      2-benzothiazole                                                                             --CH.sub.3 (CH.sub.2).sub.3 CH.sub.3                     k      2-benzoxazole --CH.sub.3 (CH.sub.2).sub.3 CH.sub.3                     l      3-pyridyl     --CH.sub.3 CH.sub.2 C.sub.6 H.sub.5                      m      3-(2-furanyl)phenyl                                                                         --CH.sub.3 CH.sub.2 C.sub.6 H.sub.5                      ______________________________________                                    

Triazinone and pyridazinone compounds of formula I with A=CO can beconverted to the corresponding thiocarbonyl analogs of Formula I withA=CS by treatment with a suitable reagent such as Lawesson's Reagent(2,4-bis(4-methoxy-phenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide).The following examples illustrate this method.

EXAMPLE 102 1-Phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-thione. Formula I,A=CS, B=NH, R₁ =phenyl, R₂ =Z=H.

To a suspension of 1-phenyl-2H, 4H-triazin-3-one (4.0 g, 23 mmol) intoluene (150 mL) was added Lawesson's Reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide,10,0 g). The mixture was heated at 80° C. for 15 h, then cooled and amixture of methanol and dichloromethane (1:1, 50 mL) and water (100 mL)was added. The organic layer was collected and concentrated to provide aresidue which was purified by chromatography (silica gel, 5% methanol indichloromethane) to provide the title compound (1.8 g).

m.p.=180° C.

1H NMR (300 MHz, DMSO-d₆) 2.95-3.02 (2H, m), 3.63 (2H, t, J=5 Hz),6.91-7.01 (3H, m), 7.30 (2H, t, J=7.5 Hz), 8.39 (1H, br s), 9.97 (1H, brs).

Mass spectrum (M+H)⁺ =194

Anal. Calc'd for C₉ H₁₁ N₃ S: C, 55.93; H, 5.74; N, 21.74.

Anal found: C, 55.16; H, 5.66; N, 21.04.

EXAMPLE 103 1-(3-Chlorophenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-thioneFormula I, A=CS, B=NH, R₁ =3chlorophenyl, R₂ =Z=H

The title compound was prepared according in an analogous manner asExample 102, except1-(3-chlorophenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-one was used insteadof 1-phenyl-2H,4H-triazin-3-one.

m.p.=204°-205 ° C.

1H NMR (300 MHz, DMSO-d₆) 2.97-3.05 (2H, m), 3.69 (2H, t, J=5 Hz),6.95-7.04 (3H, m), 7.32 (1H, t, J=7.5 Hz), 8.5 (1H, br s), 10.1 (1H, brs).

Mass spectrum (M+H)⁺ =228

Anal. Calc'd for C₉ H₁₀ ClN₃ S: C, 47.47; H, 4.43; N, 18.45.

Anal. found: C, 46.46; H, 4.11; N, 17.13.

EXAMPLE 104 1-phenyl-2H-tetrahydropyridazin-3-thione Formula I, A=CS,B=CH₂, R₁ =C₆ H₅, R₂ =Z=H

The title compound was prepared in an analogous manner as in Example 102except that 1-phenyl-2H-tetrahydropyridazin-3-one was used instead ofthe 1,2,4-triazin-3-one.

mp. 108° C.

¹ H NMR (300 MHz, CDCL3) 1.90 (2H, n), 2.90 (@h, t, J=7 Hz), 3.65 (2H,t, JH=7 Hz), 7.02 (2H, m), 7.35 (3H, m) 9.2 (1H, br s).

Mass spectrum M +=192

EXAMPLE 105 1-(3'-fluorophenyl-2H-tetrahydro-pyridazin-3-thione FormulaI, A=CS, B=CH₂, R₁ =3-fluorophenyl, R₂ =Z=H

The title compound was prepared in an analogous manner as in Example 102except that 3'-fluorophenyl-2H-tetrahydropyridazin-3-one was usedinstead of the 1,2,4-triazin-3-one.

mp. 108° C.

¹ H NMR (300 MHz, CDCl₃) 1.98 (2H, m), 3.65 (2H, t, J=6 Hz), 6.73 (3H,m), 7.23-7.28 (1H, d, J=6 Jz), 9.25 (1H, br s).

Mass spectrum: M+=210

EXAMPLE 106 1-(3'-methylphenyl)-2H-tetrahydro-pyridazin-3-thione FormulaI, A=CS, B=CH₂, R₁ =3 -methylphenyl, R₂ =Z=H

The title compound was prepared in an analogous manner as in Example 102except that 1-(3'methylphenyl)-2H-tetrahydropyridazin-3-one was usedinstead of the 1,2,4-triazin-3-one.

mp 1241/2

¹ H NMR (300 MHz, CDCl 1.88 (2H, m), 2.34 (3H, s), 2.93 (2H, t, J=7.5Hz), 7.22 (1H, m), 9.24 (1H, br s).

Mass spectrum: M+=206

The following compounds of Formula I listed in Table 9, can be preparedin an analogous manner as described for Example 102.

                  TABLE 9                                                         ______________________________________                                        Formula I compounds                                                           ______________________________________                                        1-(3'-ethylphenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-thione                    Formula I, A = CS, B = NH, R1 = 3-ethylphenyl, R.sub.2 = Z = H                1-(4'-phenoxyphenyl)-5-methyl-2H,4H-tetrahydro-1,2,4-                         triazin-3-thione                                                              Formula I, A = CS, B = NH, R.sub.1 = 4-phenoxyphenyl,                         R.sub.2 = 5-CH.sub.3, Z = H                                                   1-(3-methoxyphenyl)-4-methyl-2H-tetrahydro-1,2,4-triazin-3-                   thione                                                                        Formula I, A = CS, B = NCH.sub.3, R.sub.1 = 3-methoxyphenyl,                  R.sub.2 = Z = H                                                               4-phenyl-3H-trihydro-1,3,4-oxadiazin-2-thione                                 Formula I, A = CS, B = O, R.sub.1 = phenyl, R.sub.2 = Z                       ______________________________________                                        = H                                                                       

The following compounds shown in Table 10 are prepared in an analogousmanner as Example 102 by applying the method to the appropriatetriazinones of Formula V

                                      TABLE 10                                    __________________________________________________________________________    Formula I, A = CS, B = NR.sub.4, Z = H, compounds                             __________________________________________________________________________    Example                                                                            R.sub.1   R.sub.2 =      R.sub.4 =                                       __________________________________________________________________________    a    meta-chlorophenyl                                                                       --CH.sub.2 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                        b    2-pyridyl --CH.sub.3     CH.sub.2 OCH.sub.2 C.sub.6 H.sub.5              c    4-pyridyl --CH.sub.2 (CH.sub.3).sub.2                                                                  CH.sub.2 C.sub.6 H.sub.5                        d    4-pyridyl --CH.sub.3     CH.sub.2 C.sub.6 H.sub.5                        e    2-pyridyl --CH.sub.3     CH.sub.2 C.sub.6 H.sub.5                        f    2-benzothiophenyl                                                                       --CH.sub.3     CH.sub.2 C.sub.6 H.sub.5                        g    3-(2-pyridyl)phenyl                                                                     --CH.sub.3     CH.sub.2 C.sub.6 H.sub.5                        h    4-pyridyl --CH.sub.3     (CH.sub.2).sub.3 CH.sub.3                       i    2-quinoyl --CH.sub.3     CH.sub.2 C.sub.6 H.sub.5                        j    2-benzothiazole                                                                         --CH.sub.3     (CH.sub.2).sub.3 CH.sub.3                       k    2-benzoxazole                                                                           --CH.sub.3     (CH.sub.2).sub.3 CH.sub.3                       l    3-pyridyl --CH.sub.3     CH.sub.2 C.sub.6 H.sub.5                        m    3-(2-furanyl)phenyl                                                                     --CH.sub.3     CH.sub.2 C.sub.6 H.sub.5                        __________________________________________________________________________    example                                                                            R.sub.1   R.sub.2        R.sub.4  = H                                    __________________________________________________________________________    n    4-pyridyl --CH.sub.2 CH.sub.2 CH.sub.2 OH                                o    2-benzoxazole                                                                           --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 OH                       p    meta-chlorophenyl                                                                       --CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.3                        q    meta-methylphenyl                                                                       --CH.sub.2 CH.sub.2 NHC(═NH)NH.sub.2                       r    2-pyridyl --CH.sub.2 CH.sub.2 CH.sub.2 C(═NOH)CH.sub.3               s    3-chlorophenyl                                                                          --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 SO.sub.2 CH.sub.3        t    3-methylphenyl                                                                          --CH.sub.2 CH.sub.2 SO.sub.2 CH.sub.3                          u    2-pyridyl --CH.sub.2 CH.sub.2 SOC.sub.6 H.sub.5                          v    meta-methylphenyl                                                                       --CN                                                           w    meta-chlorophenyl                                                                       --CH.sub.2 OCH.sub.2 CH.sub.2 OH                               x    meta-chlorophenyl                                                                       --C═NOCH.sub.3                                             y    meta-methylphenyl                                                                       --CH.sub.2 OCH.sub.2 CH═CH.sub.2                           z    meta-chlorophenyl                                                                       --CH.sub.2 OCH.sub.2 C.tbd.CH                                  aa   2-benzothiazole                                                                         --COCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                        __________________________________________________________________________

h) Scheme XII

Triazinone compounds of the Formula VI can be converted to the4-substituted analogs of Formula V as outlined in Scheme XII. Treatmentof a triazinone with an acylating reagent such as a carboxylic anhydridein the presence of a suitable base provides the intermediate47.Selective hydrolysis of the 2-acyl substituent provides the triazinonesof Formula V. The intermediates 47 can be converted in vivo to thecorresponding triazinones V and therefore they can serve as prodrugprecursors to active inhibitors of 5-lipoxygenase. ##STR43##

EXAMPLE 107 4-Acetyl-1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V , R₁ =phenyl, R₄ =acetyl, R₂ =H

a). 1-Phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-one (3.24 g, 0.018 mole)was added to a stirred suspension of sodium hydride (60% in mineral oil,1.70 g, 0.04 mol) in dry benzene (250 mL). The mixture was stirred atroom temperature for 15 min. and then acetic anhydride (4.10 g, 0.04mole) was added. The mixture was stirred at 110° C. for 24 hrs., cooledand poured into dichloromethane (300 mL). A saturated aqueous solutionof NH₄ CI (75 mL) was added, the organic layer was dried over MgSO₄,concentrated and the residue titrurated in ether-hexane to give thediacetyl derivative (2.47 g).

m. p.=82°-85° C.

¹ H NMR (300 MHz, DMSO-d₆) 2.27 (3H, s), 2.44 (3H, s), 3.44-3.83 (3H,m), 4.41 (1H, br s), 6.88-6.97 (3H, m), 7.25-7.35 (2H, t, J=9.0 Hz).

Mass spectrum: (M+H)⁺ =262

Anal. Calc'd for C₁₃ H₁₅ N₃ O₃ : C, 59.76; H, 5.79; N, 16.08

Anal. Found: C, 59.47; H, 5.90; N, 16.19

b). The diacetyl derivative from part a (1.93 g, 0.007 mole) was treatedwith methanol (40 mL), water (8 mL) and sodium bicarbonate (0.10 g). Themixture was stirred at room temperature for 24 h followed byconcentration in vacuo. The residue was extracted with dichloromethane(50 mL), the extract was dried over MgSO₄ and concentrated. Theresulting crude product was purified by chromatography (silica gel, CH₂Cl₂ --Et₂ O, (1:1) then CH₂ Cl₂ --CH₃ OH, 9:1) to give 0.75 g of themonoacetyl product.

m. p.=144°-147° C.

¹ H NMR (300 MHz, DMSO-d₆) 2.36 (3H, s), 3.49 (2H, t, J=6.0 Hz), 3.87(2H, t, J=6.0 Hz), 6.92 (1H, t, J=7.5 Hz), 7.05 (2H, d, J=7.5 Hz), 7.29(2H, t, J=7.5 Hz), 9.67 (1H, s).

Mass spectrum: (M+H)⁺ =220

Anal. Calc'd for C₁₁ H₁₃ N₃ O₂ : C, 60.26; H, 5.98; N, 19.17.

Anal. Found: C, 59.95; H, 5.98; N, 19.06.

EXAMPLE 1084-Acetyl-5-methyl-1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-one FormulaV , R₁ =phenyl, R₄ =acetyl, R₂ =methyl

The title compound was prepared according to Scheme XII in an analogousmanner as Example 107, except5-methyl-1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-one was used in parta instead of 1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-one.

m.p.=93°-97° C.

¹ H NMR (300 MHz, DMSO-d₆) 1.08 (3H, d, J=6.0 Hz), 2.18 (3H, s), 3.41(1H, m), 4.24-4.40 (2H, m), 6.86 (1H, t, J=7.5 Hz), 7.03 (2H, d, J=7.5Hz), 7.26 (2H, t, J=7.5 Hz), 9.92 (1H, s).

Mass spectrum: (M+H)⁺ =234

Anal. Calc'd. for C₁₂ H₁₅ N₃ O₂ : C, 61.79; H, 6.48; N, 18.01.

Anal. Found: C, 61.91; H, 6.61; N, 18.06.

EXAMPLE 109 4-Isobutyryl-1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V , R₁ =phenyl, R₄ =isobutyryl, R₂ =H

The title compound was prepared according to Scheme XII in an analogousmanner as Example 107 except isobutyric anhydride was used in part ainstead of acetic anhydride.

m.p.=125°-126° C.

¹ H NMR (300 MHz, DMSO-d₆) 0.95 (6H, d, J=6 Hz), 3.48 (2H, t, J=7.0 Hz),3.66-3.72 (1H, m), 3.87 (2H, t, J=7.0 Hz), 6.89-7.92 (1H, m), 7.03 (2H,d, J=5 Hz), 7.29 (2H, t, J=5 Hz), 9.69 (1H, s).

Mass spectrum: M+=248

Anal. Calc'd. for C₁₃ H₁₇ N₃ O₂ : C, 63.14; H, 6.93; N, 16.99.

Anal. Found: C, 63.17; H, 7.08; N, 16.48.

EXAMPLE 110 4-Propionyl-1-phenyl-2H,4H-tetrahydro-1,2,4-triazin-3-oneFormula V , R₁ =phenyl, R₄ =propionyl, R₂ =H

The title compound was prepared according to Scheme XII in an analogousmanner as Example 107 except propionic anhydride was used in part ainstead of acetic-anhydride.

m.p.=125°-126° C.

¹ H NMR (300 MHz, DMSO-d₆) 0.98 (3H, t, J=7.5 Hz), 2.81 (2H, q, J=7 Hz),3.5 (2H, t, J=6 Hz), 3.87 (2H, t, J=6 Hz), 6.91 (1H, t, J=7.5 Hz), 7.04(2H, d, J=7 Hz), 7.28 (2H, t, J=8 Hz), 9.63 (1H, br s).

Mass spectrum: M⁺ =234

Anal Calc'd. for C₁₂ H₁₄ N₃ O₂ : C, 62.05; H, 6.08; N, 18.09.

Anal. Found: C, 62.33; H, 6.62; N, 18.03.

EXAMPLE 1114-Acetyl-1-(3-chlorophenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-one FormulaV , R₁ =3-chlorophenyl, R₄ =acetyl, R₂ =H

The title compound was prepared according to Scheme XII in an analogousmanner as Example 107 except1-(3-chlorophenyl)-2H,4H-tetrahydro-1,2,4-triazin-3-one was used in parta instead of 1-phenyl-2H,4H-tetrahydro-1,2,4-triazinone.

m.p.=162° C.

¹ H NMR (300 MHz, DMSO-d₆) 2.35 (3H, s), 3.52 (2H, t,J=6 Hz), 3.92 (2H,t, J=6 Hz), 6.95 (1H, d, J=7.0 Hz), 7.03 (1H, d, J=7.0 Hz), 7.1 (1H, s),7.3 (1H, t, J=7.5 Hz), 9.75 (1H, s).

Mass spectrum: M⁺ =254

Anal. Calc'd for C₁₁ H₁₂ Cl₁ N₃ O₂ : C, 52.08; H, 4.77; N, 16.56.

Anal. Found: C, 51.68; H, 4.63; N, 16.46.

The following compounds of general Formula V shown in Table 11 may beprepared according to the method of scheme XII in an analagous manner asExample 107 by applying the method to the appropriate triazinone ofFormula VI.

                  TABLE 11                                                        ______________________________________                                        Formula V compounds.                                                          Example                                                                              R.sub.1        R.sub.2   R.sub.4                                       ______________________________________                                        a      meta-chlorphenyl                                                                             CH.sub.3  CH.sub.2 C.sub.6 H.sub.5                      b      2-pyridyl      CH.sub.3  CH.sub.2 OCH.sub.2 C.sub.6 H.sub.5            c      4-pyridyl      CH.sub.2 (CH.sub.3).sub.2                                                               CH.sub.3                                      d      4-pyridyl      CH.sub.3  CH.sub.3                                      e      2-pyridyl      CH.sub.3  CH(CH.sub.3).sub.2                            f      2-benzothiophenyl                                                                            CH.sub.3  CH.sub.2 C.sub.6 H.sub.5                      g      3-(-2-pyridyl)phenyl                                                                         CH.sub.3  CH.sub.2 C.sub.6 H.sub.5                      h      4-pyridyl      CH.sub.3  (CH.sub.2).sub.3 CH.sub.3                     i      2-quinoyl      CH.sub.3  CH.sub.2 C.sub.6 H.sub.5                      j      2-benzothiazole                                                                              CH.sub.3  CH.sub.3                                      k      2-benzoxazole  CH.sub.3  CH.sub.3                                      l      3-pyridyl      CH.sub.3  OCH.sub.3                                     m      3-(2-furanyl)phenyl                                                                          CH.sub.3  OCH.sub.3                                     n      4-pyridyl      CH.sub.3  (CH.sub.2).sub.2 CO.sub.2 H                   o      meta-chlorophenyl                                                                            CH.sub.3  (CH.sub.2).sub.4 CO.sub.2 H                   p      2-benzothiophenyl                                                                            CH.sub.3  (CH.sub.2).sub.4 CO.sub.2 H                   q      meta-chlorophenyl                                                                            CH.sub.3  (CH.sub.2).sub.4 CO.sub.2 H                   r      meta-chlorophenyl                                                                            CH.sub.3  CH.sub.2 OH                                   s      4-pyridyl      CH.sub.3  (CH.sub.2).sub.3 CH.sub.2 OH                  ______________________________________                                    

III. Oxapyridazinone Synthesis

Oxapyridazinone compounds of this invention having the general FormulaVII can be prepared according to Scheme XIII. The aryl hydrazine (48) isreacted with a substituted 2-bromoethanol derivative (49) anddiisopropylethylamine to produce the hydroxyhydrazine intermediate (50).The hydroxyhydrazine (50) is heated with acid and then neutralized toprovide the hydroxyhydrazine which is reacted with carbonyl diimidazole(CO(IM)₂) or phosgene to produce the oxapyridazinone (VII). ##STR44##

EXAMPLE 112 4-phenyl-3H-trihydro-1,3,4-oxadiazin-2-one Formula VII, R₁=phenyl, R₂ =H

a) Acetyl-2-(2'-hydroxy)ethyl-2-phenyl hydrazine

A solution of acetyl 2-phenylhydrazine (75.3 g, 0.5 mole),2-bromoethanol (64.0 g, 0.55 mole) and diisopropylethylamine (68.0 g,0.55 mole) in toluene (300 mL) was refluxed with stirring for 48 hoursunder nitrogen. The mixture was allowed to cool to room temperature anddichloromethane (500 mL) and water (250 mL) were added. The organiclayer was washed with water (2×250 mL), dried over MgSO₄, filtered andevaporated to give a brown oil. This residue was purified by columnchromatography (silica gel, 10% methanol in dichloromethane) to providethe desired intermediate (30.4 g).

b) 1-(2'-hydroxy)ethyl-1-phenylhydrazine

The product from part a (13.5 g, 0.07 mole) in 6N HCl (50 mL) wasrefluxed under nitrogen for 2 hours. The mixture was cooled in an icebath, and 6N KOH was added until the solution was neutral (pH 7). Themixture was extracted with ethyl acetate (5×100 mL) and the combinedorganic extract was dried over MgSO₄, filtered and evaporated to givethe desired intermediate (10.2 g).

c) 4-phenyl-3H-trihydro-1,3,4-oxadiazin-2-one

To the product of part b (10.2 g, 0.067 mole) dissolved intetrahydrofuran (50 mL) was added carbonyl diimidazole (10.9 g, 0.067mole), and the mixture was stirred at room temperature under nitrogenfor 3 hours. Dichloromethane (100 mL) was added, and the organicsolution was washed with water (2×50 mL) and aqueous saturated NaCl (50mL), dried over MgSO₄, filtered and evaporated to give a thick oil (9.4g). The residue was purified by column chromatography (silica gel, 7%methanol in dichloromethane) followed by recrystallization from ether toprovide the desired product (2.28 g), mp 99°-100° C.

NMR (300 MHz,CDCl₃) 3.74 (2H, t, J=10 Hz), 4.29 (2H t, J=10 Hz), 7.08(3H, m), 7.23 (1H, br), 7.33 (2H, m).

Mass spectrum: M+=178.

The following compounds of general Formula VII, listed in Table 12 , maybe prepared according to Scheme XIII in an analogous manner as describedfor Example 112.

                  TABLE 12                                                        ______________________________________                                        Formula VII compounds                                                         ______________________________________                                        4-(3'-ethylphenyl)-3H-trihydro-1,3,4-oxadiazin-2-one                          Formula VII, R.sub.1 = 3-ethylphenyl, R.sub.2 = H                             4-(4'-phenoxyphenyl)-3H-trihydro-1,3,4-oxadiazin-2-one                        Formula VII, R.sub.1 = 4-phenoxyphenyl, R.sub.2 = H                           4-(phenyl)-6-methyl-3H-trihydro-1,3,4-oxadiazin-2-one                         Formula VII, R.sub.1 = phenyl, R.sub.2 = 6-methyl                             4-(phenyl)-6-butyl-3H-trihydro-1,3,4-oxadiazin-2-one                          Formula VII, R.sub.1 = phenyl, R.sub.2 = 6-butyl                              4,6-diphenyl-3H-trihydro-1,3,4-oxadiazin-2-one                                Formula VII, R.sub.1 = phenyl, R.sub.2 = phenyl                               ______________________________________                                    

IV Synthesis of Compound Containing Metabolically Cleaveable Groups

Pyridazinone, triazinone, and oxapyridazinone compounds of thisinvention of the general Formula I with Z being a metabolicallycleaveable group can be prepared from compounds of the general Formula Iwith Z=H. A compound of Formula I is condensed with an electrophile Z-X(where X is a leaving group such as halogen, carbonyl, acyl chloride, oran alkyl or aryl formyl chloride, or the like) in the presence of ansuitable base to produce a compound of Formula I. The following examplesillustrate the above method.

EXAMPLE 113 1-phenyl-2-benzyloxymethyl-2H-tetrahydropyridazin-3-oneFormula I, R₁ =phenyl, R₂ =H, Z=CH₂ OCH₂ C₆ H₅, A=CO, B=CH₂

To a solution of 1-phenyl-2H-tetrahydropyridazin-3-one (1.76 g, 0.01mole) in tetrahydrofuran (50 mL) at -78° C. under nitrogen was addedwith stirring a solution of tert-butyllithium (7 mL of 1.6M pentanesolution, 0.011 mole). The mixture was allowed to warm to 5° C. afterwhich benzyl chloromethyl ether (1.6g, 0.011 mole) was added. Themixture was stirred at 5° C. for two hours and 10% aqueous sodiumbicarbonate (20 mL) was added followed by dichloromethane (50 mL). Theorganic layer was separated, dried over MgSO₄, filtered and evaporatedto give a residue. Purification by column chromatography (silica gel,105 ether in dichloromethane) gave the desired product (2.0 g)

¹ H NMR (300 MHz, CDCl₃) 2.07 (2H, m), 2.36 (2H, t, J=7.5 Hz), 3.74 (2H,t, J=6.5 Hz), 4.72 (2H, s), 5.03 (2H, s), 6.92 (3H, m), 7.32 (7H, m).

Mass spectrum: M+=296

EXAMPLE 114 1-phenyl-2-benzyl-2H-tetrahydropyridazin-3-one Formula I, R₁=phenyl, R₂ =H, Z=CH₂ C₆ H₅, A=CO, B=CH₂

The title compound was prepared in an analogous manner as Example 113except benzylbromide was used instead of benzyl chloromethyl ether.

¹ H NMR (300 MHz, CDCl₃) 1.96 (2H, m), 2.36 (2H, t, J=7.5 Hz), 3.42 (2H,t, J=7 Hz), 4.67 (2H, s), 6.87 (2H,

d, J=8 Hz), 6.96 (1H, t, J=7.5 Hz), 7.24-7.42 (7H, m).

Mass spectrum: M+=266

EXAMPLE 115 1-phenyl-2-carbomethoxy-2H-tetrahydropyridazin-3-one FormulaI, R₁ =phenyl, R₂ =H, Z=COOCH₃, A=CO, B=CH₂

The title compound was prepared in an analogous manner as Example 113except methoxy chloroformate was used instead of benzyl chloromethylether.

¹ H NMR (300 MHz, CDCl₃) 2.20 (2H, m), 2.37 (2H, m), 3.88 (5H, m), 6.84(2H, m), 6.94 (1H, m), 7.30 (2H, m).

Mass spectrum: M+=234

EXAMPLE 116 1-phenyl-2-propionyl-2H-tetrahydropyridazin-3-one Formula I,R₁ =phenyl, R₂ =H, Z=COCH₂ CH₃, A=CO, B=CH₂

The title compound was prepared in an analogous manner as Example 113except propionyl chloride was used instead of benzyl chloromethyl ether.

¹ H NMR (300 MHz, CDCl₃) 1.19 (3H, t, J=7.5 Hz), 2.05 (2H, m), 2.35 (2H,m), 2.84 (2H, m), 3.46 (1H, m), 4.17 (1H, m), 6.78 (2H, m), 6.92 (1H,m), 7.29 (2H, m).

Mass spectrum: M+=233

EXAMPLE 117 1-phenyl-2-benzoyl-2H-tetrahydropyridazin-3-one Formula I,R₁ =phenyl, R₂ =H, Z=COC₆ H₅, A=CO, B=CH₂

The title compound was prepared in an analogous manner as Example 113except benzoyl chloride was used instead of benzyl chloromethyl ether.

¹ H NMR (300 MHz, CDCl₃) 2.28 (2H, m), 2.46 (2H, t, J=7.5 Hz), 3.73 (2H,m), 6.94 (3H, m), 7.30 (2H, m), 7.42 (2H, m), 7.52 (1H, m), 7.69 (2H,m).

Mass spectrum: M+=280

EXAMPLE 1181-phenyl-2-methoxycarbonylmethyl-2H-tetrahydropyridazin-3-one Formula I,R₁ =phenyl, R₂ =H, Z=CH₂ CO₂ CH₃, A=CO, B=CH₂

The title compound was prepared in an analogous manner as Example 113except methyl bromoacetate was used instead of benzyl chloromethylether.

¹ H NMR (300 MHz, CDCl₃) 2.04 (2H, m), 2.43 (2H, t, J=7.5 Hz), 3.76 (3H,s), 3.89 (2H, m), 4.31 (2H, s), 6.88 (2H, m), 6.98 (1H, m), 7.32 (2H,m).

Mass spectrum: M+=248

EXAMPLE 1191-(3'-benzyloxymethylphenyl)-2-benzyl-2H-tetrahydropyridazin-3-oneFormula I, R_(i) =3-benzyloxymethylphenyl, R₂ =H, Z=CH₂ C₆ H₅, A=CO,B=CH₂

The title compound was prepared in an analogous manner as Example 113except 1-(3'-benzyloxymethylphenyl)-2H-tetrahydropyridazin-3-one andbenzyl bromide were used instead of1-phenyl-2H-tetrahydropyridazin-3-one and benzyl chloromethyl ether.

¹ H NMR (300 MHz, CDCl₃) 1.83-1.94 (2H, m), 2.22 (2H, t, J=7.5 Hz), 3.49(2H, m), 4.49 (2H, s), 4.52 (2H, s), 4.59 (2H, s), 6.80-6.95 (3H, m),7.20-7.42 (11H, m).

Mass spectrum: M+=386

The following compounds of general Formula I listed in Table 13, may beprepared in an analogous manner as described for Example 113.

                  TABLE 13                                                        ______________________________________                                        Formula I compounds                                                           ______________________________________                                        1-(3'-ethylphenyl)-2-benzoyl-4-methyltetrahydro-                              pyridazin-3-one                                                               Formula I, R.sub.1 = 3-ethylphenyl, R.sub.2 = H, Z = COC.sub.6 H.sub.5, A     CO, B = CHCH.sub.3                                                            1-(4'-phenoxyphenyl)-2-propionyl-5-methyltetrahydro-                          pyridazin-3-one                                                               Formula I, R.sub.1 = 4-phenoxyphenyl, R.sub.2 = 5-CH.sub.3, Z =               --COCH.sub.2 CH.sub.3, A = CO, B = CH.sub.2                                   1-(4'-phenoxyphenyl)-2-methoxymethyl-4-benzyltetrahydro-                      pyridazin-3-one                                                               Formula I, R.sub.1 = 4-phenoxyphenyl, R.sub.2 = H, Z = CH.sub.2 OCH.sub.3,     A =                                                                          CO, B = CHCH.sub.2 C.sub.6 H.sub.5                                            1-(3-methoxyphenyl)-2-thiophenylmethyltetrahydro-                             pyridazin-3-one                                                               Formula I, R.sub.1 = 3-methoxyphenyl, R.sub.2 = H, Z = CH.sub.2 SC.sub.6      H.sub.5,                                                                      A = CO, B = CH.sub.2                                                          4-phenyl-3-benzoyltrihydro-1,3,4-oxadiazin-2-one                              Formula I, R.sub.1 = phenyl, R.sub.2 = H, Z = COC.sub.6 H.sub.5, A = CO,      B = O                                                                         4-(3'-ethylphenyl)-3-benzyl-6-methyltrihydro-1,3,4-                           oxadiazin-2-one                                                               Formula I, R.sub.1 = 3-ethylphenyl, R.sub.2 = 6-CH.sub. 3, Z = CH.sub.2       C.sub.6 H.sub.5, A =                                                          CO, B = O                                                                     1-phenyl-2-benzoyl-4-methyltetrahydro-1,2,4-triazin-3-one                     Formula I, R.sub.1 = phenyl, R.sub.2 = H, Z = COC.sub.6 H.sub.5, A = CO,      B =                                                                           NCH.sub.3                                                                     1-(3'-ethylphenyl)-2-benzyl-4-ethyltetrahydro-1,2,4-                          triazin-3-one                                                                 Formula I, R.sub.1 = 3-ethylphenyl, R.sub.2 = H, Z = CH.sub.2 C.sub.6         H.sub.5, A =                                                                  CO, B = NCH.sub.2 CH.sub.3                                                    ______________________________________                                    

INHIBITION OF 5-LIPOXYGENASE

Inhibition of 5-lipoxygenase activity was determined using the 20,000×gsupernatant from homogenized RBL-1 cells in a similiar manner as thatdescribed by Dyer and coworkers (Dyer, R. D.; Haviv., F.; Hanel, A. M.;Bornemeier, D. A.; Carter, G. W. Fed. Proc., Fed.Am.Soc. Exp. Biol.1984, 43, 1462a). Inhibitory potencies for representative examples ofthis invention are listed in Table 14. IC₅₀ values (concentration ofcompound producing 50% enzyme inhibition) were calculated by linearregression analysis of percentage inhibition versus log inhibitorconcentration plots.

                  TABLE 14                                                        ______________________________________                                        In vitro 5-lipoxygenase inhibitory                                            potency of compounds of this invention.                                       Example  IC.sub.50 (μM)                                                                          Example  IC.sub.50 (μM)                              ______________________________________                                         1       11            3       6                                               6       2             8       5                                              10       3            15       6                                              16       5            24       3                                              26       1            38       0.6                                            40       0.5          46       2.5                                            51       10           85       3                                              68       21           86       7                                              70       15           87       7                                              73       5            88       19                                             74       13           90       26                                             75       14           99       8                                              76       17           102      17                                             78       6            103      5                                              79       1            106      1                                              80       12           107      3                                              81       11           109      1                                              82       7            111      1                                              83       2            113      71                                             ______________________________________                                    

INHIBITION OF LEUKOTRIENE BIOSYNTHESIS

Inhibition of the biosynthesis of leukotrienes in vivo after oraladministration of compound was determined using a rat peritonealanaphylaxis model in a similiar manner as that described by Young andcoworkers (Young, P. R.; Dyer, R. D.; Carter, G. W. Fed. Proc., Fed. AmSoc.Exp. Biol. 1985, 44 1185). In this model rats were injectedintraperitoneally (ip) with rabbit antibody to bovine serum albumin(BSA) and three hours later injected ip with BSA to induce anantigen-antibody response. Rats were sacrificed 15 minutes after thischallenge and the peritoneal fluids were collected and analyzed forleukotriene levels. Test compounds were administered by gavage one hourprior to the antigen challenge. Inhibitory potencies for representativeexamples of this invention are listed in Table 15. Percent inhibitionvalues were determined by comparing the treatment group to the mean ofthe control group. From the results of this assay it is demonstratedthat compounds of this invention are orally effective in preventing thein vivo biosynthesis of leukotrienes.

                  TABLE 15                                                        ______________________________________                                        In Vivo inhibition of leukotriene                                             biosynthesis by oral administration                                                      % inhibition at                                                    Example    200 micro mol/kq/oral dose                                         ______________________________________                                        68         85                                                                 70         66                                                                 73         46                                                                 74         58                                                                 75         73                                                                 78         80                                                                 81         84                                                                 111        74                                                                 ______________________________________                                    

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. These salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as loweralkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides, and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl., and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Othersalts include salts with alkali metals or alkaline earth metals, such assodium, potassium, calcium or magnesium or with organic bases.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

What is claimed is:
 1. A compound of the formula ##STR45## wherein X isoxygen or sulfur; R¹ is selected from the group consistingofbenzofuranyl, 2-benzoxazolyl; dibenzofuranyl, dibenzopyrrolyl,optionally substituted with alkyl of from one to four carbon atoms,fluorenyl, indanyl, N-morpholinyl, tetrahydronaphthyl, 2-, 3- or4-pyridyl, optionally substituted by alkyl of from one to four carbonatoms and nitro, pyrimidyl; quinolinyl; thianaphthyl, phenyl; and phenylsubstituted byalkyl of from one to twelve carbon atoms, alkoxy of fromone to twelve carbon atoms, alkoxycarbonyl of from two to six carbonatoms, benzyl, cyano, halogen, hydroxymethyl, methylsulfonyl,methylthio, phenoxy, trifluoromethyl, and ##STR46## R² is selected fromthe group consisting of hydrogen, alkyl of from one to twelve carbonatoms, optionally substituted withhydroxy, alkoxy of from one to fourcarbon atoms, benzoxy, alkylthio of from one to four carbon atoms,phenylthio, alkanoyl of from two to four carbon atoms, or dialkylamino,alkylenyl of from two to four carbon atoms, alkanoyl of from one to fourcarbon atoms, benzoyl, alkoxy of from one to twelve carbon atoms, cyano,phenyl, benzyl, and thienyl; and Z is selected from the group consistingofhydrogen, a pharmaceutically acceptable cation, and a metabolicallycleavable group selected fromacetyl, methoxycarbonyl, benzoyl, --COR,--COOR, --CH₂ COOR, --C(O)NRR, --CH₂ C(O)NRR, --CH₂ OR, and --CH₂ SR,where R is selected at each occurrence from alkyl of from one to twelvecarbon atoms, phenyl, and phenyl substituted with halogen, alkyl of fromone to twelve carbon atoms, or alkoxy of from one to twelve carbonatoms.
 2. A compound of the formula ##STR47## where X is oxygen orsulfur; R¹ is selected from the group consisting ofphenyl; and phenylsubstituted byalkyl of from one to twelve carbon atoms, alkoxy of fromone to twelve carbon atoms, alkoxycarbonyl of from two to six carbonatoms, benzyl, cyano, halogen, hydroxymethyl, methylsulfonyl,methylthio, phenoxy, trifluoromethyl, and ##STR48## R² is selected fromthe group consisting of hydrogen, alkyl of from one to twelve carbonatoms, optionally substituted withhydroxy, alkoxy of from one to fourcarbon atoms, benzoxy, alkylthio of from one to four carbon atoms,phenylthio, alkanoyl of from two to four carbon atoms, or dialkylamino,alkylenyl of from two to four carbon atoms, alkanoyl of from one to fourcarbon atoms, benzoyl, alkoxy of from one to twelve carbon atoms, cyano,phenyl, benzyl, and thienyl; and Z is selected from the group consistingofhydrogen, a pharmaceutically acceptable cation, and a metabolicallycleavable group selected fromacetyl, methoxycarbonyl, benzoyl, --COR,--COOR, --CH₂ COOR, --C(O)NRR, --CH₂ C(O)NRR, --CH₂ OR, and --CH₂ SR,where R is selected at each occurrence from alkyl of from one to twelvecarbon atoms, phenyl, and phenyl substituted with halogen, alkyl of fromone to twelve carbon atoms, or alkoxy of from one to twelve carbonatoms.
 3. A compound of the formula ##STR49## where X is oxygen orsulfur; R¹ is selected from the group consisting ofbenzofuranyl,2-benzoxazolyl; dibenzofuranyl, dibenzopyrrolyl, optionally substitutedwith alkyl of from one to four carbon atoms, fluorenyl, indanyl,N-morpholinyl, tetrahydronaphthyl, 2-, 3- or 4-pyridyl optionallysubstituted by alkyl of from one to four carbon atoms and nitro,pyrimidyl; quinolinyl; thianaphthyl; R² is selected from the groupconsisting ofhydrogen, alkyl of from one to twelve carbon atoms,optionally substituted withhydroxy, alkoxy of from one to four carbonatoms, benzoxy, alkylthio of from one to four carbon atoms, phenylthio,alkanoyl of from two to four carbon atoms, or dialkylamino, alkylenyl offrom two to four carbon atoms, alkanoyl of from one to four carbonatoms, benzoyl, alkoxy of from one to twelve carbon atoms, cyano,phenyl, benzyl, and thienyl; and Z is selected from the group consistingofhydrogen, a pharmaceutically acceptable cation, and a metabolicallycleavable group selected fromacetyl, methoxycarbonyl, benzoyl, --COR,--COOR, --CH₂ COOR, --C(O)NRR, --CH₂ C(O)NRR, --CH₂ OR, and --CH₂ SR,where R is selected at each occurrence from alkyl of from one to twelvecarbon atoms, phenyl, and phenyl substituted with halogen, alkyl of fromone to twelve carbon atoms, or alkoxy of from one to twelve carbonatoms.
 4. A pharmaceutical composition useful for inhibitinglipoxygenase activity in humans and lower mammals comprising alipoxygenase inhibiting effective amount of a compound as defined byclaim 1 in combination with a pharmaceutically acceptable carrier.
 5. Amethod of inhibiting lipoxygenase activity in a human or lower mammal inneed of such treatment comprising administering an effective amount of acompound as defined by claim 1.